Aryl sulfonamides as blt1 antagonists

ABSTRACT

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are antagonists of leukotriene B 4  receptor 1 (BLT1) and may be useful in the treatment, prevention and suppression of diseases mediated by the leukotriene B 4  receptor 1 (BLT1). The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Non-alcoholic fatty liver disease/nonalcoholic steatohepatitis, metabolic syndrome, atherosclerosis, and cancer.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disease derived from multiple causative factorsand characterized by elevated levels of plasma glucose (hyperglycemia)in the fasting state or after administration of glucose during an oralglucose tolerance test. There are two generally recognized forms ofdiabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus(IDDM), patients produce little or no insulin, the hormone whichregulates glucose homeostasis. In Type 2 diabetes, ornoninsulin-dependent diabetes mellitus (NIDDM), insulin is stillproduced in the body, however patients have a resistance to the effectsof insulin in stimulating glucose and lipid metabolism in theinsulin-sensitive tissues such as muscle, liver and adipose. Early stageof type 2 diabetes patients often have normal levels of insulin, and mayhave hyperinsulinemia (elevated plasma insulin levels), as the isletbeta cells try to compensate for the reduced effectiveness of insulin bysecreting increased amounts of insulin. This lack of responsiveness toinsulin results in insufficient insulin-mediated activation of uptake,oxidation and storage of glucose in muscle; inadequate insulin-mediatedrepression of lipolysis in adipose tissue and glucose output from theliver.

Persistent or uncontrolled hyperglycemia is associated with increasedand premature morbidity and mortality. Impaired glucose homeostasis isassociated both directly and indirectly with obesity, hypertension, andalterations of the lipid, lipoprotein and apolipoprotein metabolism, aswell as other metabolic and hemodynamic diseases. Patients with Type 2diabetes mellitus have a significantly increased risk of macrovascularand microvascular complications, including atherosclerosis, coronaryheart disease, stroke, peripheral vascular disease, hypertension,nephropathy, neuropathy, and retinopathy. Therefore, therapeutic controlof glucose homeostasis, lipid metabolism, obesity, and hypertension arecritically important in the clinical management and treatment ofdiabetes mellitus.

Patients who have insulin resistance often have Metabolic Syndrome withcomplications including vascular dysfunctions, atherosclerosis andcoronary heart disease, (as defined in the Third Report of the NationalCholesterol Education Program Expert Panel on Detection, Evaluation andTreatment of High Blood Cholesterol in Adults (Adult Treatment PanelIII, or ATP III), National Institutes of Health, 2001, NIH PublicationNo. 01-3670).

Pharmacologic treatments for diabetes have largely focused on threeareas of pathophysiology: (1) hepatic glucose production (biguanides,such as phenformin and metformin), (2) insulin resistance (PPARagonists, such as rosiglitazone, troglitazone, engliazone,balaglitazone, and pioglitazone), (3) insulin secretion (sulfonylureas,such as tolbutamide, glipizide and glimipiride); (4) incretin hormonemimetics (GLP-1 derivatives and analogs, such as exenatide, liraglutide,dulaglutide, semaglutide, lixisenatide, albiglutide and taspoglutide);and (5) inhibitors of incretin hormone degradation (DPP-4 inhibitors,such as sitagliptin, alogliptin, vildagliptin, linagliptin, denagliptinand saxagliptin).

The two best known biguanides, phenformin and metformin, demonstratedreasonable efficacy in controlling hyperglycemia with the adverse effectof lactic acidosis and nausea/diarrhea. PPAR gamma agonists, such asrosiglitazone and pioglitazone, are modestly effective in reducingplasma glucose and hemoglobin A1C. However, the currently marketedglitazones do not greatly improve lipid metabolism and may negativelyeffect on the lipid profile. The administration of insulinsecretagogues, such as the sulfonylureas (e.g. tolbutamide, glipizide,and glimepiride) can result in hypoglycemia; their administration musttherefore be carefully controlled.

Leukotriene B₄ (LTB₄) is a pro-inflammatory lipid mediator generatedfrom arachidonic acid through the activities of 5-lipoxygenase,5-lipoxygenase activating protein (FLAP) and leukotriene A4 hydrolase(LTA4H) (Samuelsson et al., Science 1987; 237:1171-1176, Haeggstrom, JZ, J. Biol Chem. 2004; 279:50639-50642).

LTB₄ is a chemoattractant and regulates the proinflammatory cytokines bybinding to a G-protein coupled receptor leukotriene B₄ receptor 1 (BLT1)and leukotriene B₄ receptor 2 (BLT2). LTB₄ has been considered anendogenous mediator for the recruitment of inflammatory cells in acuteand chronic disease states and has been associated with inflamed tissuein rheumatoid arthritis, psoriasis, inflammatory bowel disease andasthmas; and LTB₄ receptor antagonists were developed for the treatmentof variety of inflammatory diseases (Dalvie et al., Xenobiotica, 1999,Vol. 29, No. 11, 11-23-1140). The potent biological actions of LTB₄ aremediated primarily through a high affiniity interaction with a G-proteincoupled receptor termed BLT-1 (Yokomizo et al., Nature, 1997;387:620-624). LTB₄:BLT1 plays an important role in host defense duringacute infection. Choronic activation of the LTB₄:BLT1 pathwaycontributes to the development of inflammatory diseases such asatherosclerosis and arthritis. BLT1, a high affinity receptor specificfor LTB₄, is demonstrated to express predominantly in leucocytes. BLT2,a low affinity receptor for LTB₄, is ubiquitiously expressed. In the1990s, BLT1 and dual BLT1/BLT2 antagonists were pursued for treatinginflammatory conditions including asthma, chronic obstructive pulmonarydisease, inflammatory bowel disease, cystic fibrosis, rheumaticarthritis and cancer. Recent publications suggest a potential BLT1involvement in mediating tumor progression and the blockade of LTB₄/BLT1pathways could generate benefits in controlling tumor growth (Yokota etal., Blood, 2012; 120:3444-3454; Woo-Kwang Jeon et al., Theproinflammatory LTB₄/BLT1 signal axis confers resistance toTGF-β1-induced growth inhibition by targeting Smad3 linker region,Oncotarget, Advance Publications 2015; and Wang, Luman et al., Am JRespir Crit Care Med 2012, 186: 989-998).

It was recently found that deficiency of BLT1 protects against thedevelopment of insulin resistance in diet-induced obesity by regulatingadipose tissue macrophage accumulation and inflammation ininsulin-sensitive tissues (Spite et al., J Immunol., 2011 Aug. 15,187(4), 1942-1949). The study also found that 1) BLT1 deficiencyimproves glucose and insulin-tolerance in diet induced obese mousemodel; 2) BLT1 is a key regulator of macrophage accumulation in adiposetissue and systemic insulin signaling; and 3) the BLT1 pathway pointstowards new avenues for the therapeutic management of obesity and type 2diabetes (Spite et al., J Immunol., 2011, 15, 187(4), 1942-1949).

Compounds that are antagonists of leukotriene B₄ receptor 1 (BLT1) maybe useful to treat type 2 diabetes mellitus, obesity, hypertension,dyslipidemia, cancer, and metabolic syndrome, as well as cardiovasculardiseases, such as myocardial infarction and stroke, by improving glucoseand lipid metabolism, and by improving whole body energy homeostasis.

Leukotriene B₄ (LTB₄) receptor antagonists are disclosed in: WO93/015066; WO 93/015067; WO 96/006604; WO 96/011920; WO 96/011925; WO96/41645; WO 98/011119; WO 03/007947; WO 13/106238; U.S. Pat. Nos.5,550,152; 5,552,435; 5,939,452; 6,051,601; 6,117,874; 6,133,286; US2009/054466; US 2009/253684; US 2009/227603; EP00518819; Koch et al., J.Med. Chem., 1994, Vol. 37, No. 20, pp. 3197-3199; Showell et al., J. ofPharmacology and Experimental Therapeutics, Vol. 273, No. 1, pp.176-184, 1995; Reiter et al., Bioorg. Med. Chem Lett. 8 (1998)1781-1786; Chambers et al., Bioorg. Med. Chem. Lett. 8 (1998) 1787-1790;Reiter et al., Bioorg. Med. Chem. Lett. 7 (1997) 2307-2312; Showell etal., J. of Pharmacology and Experimental Therapeutics, Vol. 285, No. 3,pp. 946-954, 1998; Dalvie et al., Xenobiotica, 1999, Vol. 29, No. 11,11-23-1140; Jones et al., Heterocycles, Vol. 53, No. 8, 2000, pp.1713-1724; and Khojasteh-Bakht et al., Xenobiotica, December 2003, Vol.33, No. 12, 1201-1210.

Hydroxy tetralins are disclosed in U.S. Pat. Nos. 5,215,989; 5,032,598;and EP 0 431 945.

SUMMARY OF THE INVENTION

The present invention relates to novel substituted compounds ofstructural formula I:

and pharmaceutically acceptable salts thereof. The compounds ofstructural formula I, and embodiments thereof, are antagonists ofleukotriene B₄ receptor 1 (BLT1 antagonists) and may be useful in thetreatment, prevention and suppression of diseases, disorders andconditions mediated by antagonism of the BLT1 receptor, such as Type 2diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia,lipid disorders, obesity, hypertension, Non-alcoholic fatty liverdisease/nonalcoholic steatohepatitis, metabolic syndrome,atherosclerosis, and cancer.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier. The present invention also relates to methods forthe treatment, control or prevention of disorders, diseases, andconditions that may be responsive to antagonism of the BLT1 receptor ina subject in need thereof by administering the compounds andpharmaceutical compositions of the present invention. The presentinvention also relates to the use of compounds of the present inventionfor manufacture of a medicament useful in treating diseases, disordersand conditions that may be responsive to the antagonism of the BLT1receptor. The present invention is also concerned with treatment ofthese diseases, disorders and conditions by administering the compoundsof the present invention in combination with a therapeutically effectiveamount of another agent that may be useful to treat the disease,disorder and condition. The invention is further concerned withprocesses for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structuralFormula I:

or a pharmaceutically acceptable salt thereof; whereinA is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-4substituents independently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, andhalogen;B is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein aryl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, halogen and CF₃, and whereinheteroaryl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, halogen, and CF₃;X is selected from the group consisting of:

(1) —NHSO₂CF₃,

(2) —NHSO₂CH₂CF₃,

(3) —NHSO₂CHF₂,

(4) —NHSO₂C₁₋₆alkyl,

(5) —NHSO₂CH₂C₃₋₆cycloalkyl, and

(6) —NHSO₂C₃₋₆cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3substituents independently selected from C₁₋₆alkyl;Z is selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆alkyl, and

(3) phenyl,

wherein alkyl and phenyl are unsubstituted or substituted with 1-4substituents independently selected from C₁₋₆alkyl;R^(a) is selected from the group consisting of:

(1) hydrogen,

(2) halogen, and

(3) C₁₋₆alkyl; and

R^(b) is selected from the group consisting of:

(1) hydrogen,

(2) halogen, and

(3) C₁₋₆alkyl.

The invention has numerous embodiments, which are summarized below. Theinvention includes the compounds as shown, and also includes individualdiastereoisomers, enantiomers, and epimers of the compounds, andmixtures of diastereoisomers and/or enantiomers thereof includingracemic mixtures.

In one embodiment of the present invention, A is selected from the groupconsisting of: aryl, and heteroaryl, wherein aryl and heteroaryl areunsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen.

In another embodiment of the present invention, A is selected from thegroup consisting of: aryl, and heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with 1-4 substituents independentlyselected from: cyclopropyl, CH₃, CH₂CH₃, —C(CH₃)₃, and F.

In another embodiment, A is selected from the group consisting of: aryland heteroaryl.

In another embodiment of the present invention, A is selected from thegroup consisting of: phenyl, and heteroaryl, wherein phenyl andheteroaryl are unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen. Inanother embodiment of the present invention, A is selected from thegroup consisting of: phenyl, and heteroaryl, wherein phenyl andheteroaryl are unsubstituted or substituted with 1-4 substituentsindependently selected from: cyclopropyl, CH₃, CH₂CH₃, —C(CH₃)₃, and F.

In another embodiment, A is selected from the group consisting of:phenyl, and heteroaryl, wherein phenyl and heteroaryl are unsubstitutedor substituted with 1-4 substituents independently selected from:C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen. In another embodiment, A isselected from the group consisting of: phenyl, and heteroaryl, whereinphenyl and heteroaryl are unsubstituted or substituted with 1-4substituents independently selected from cyclopropyl, CH₃ and F. Inanother embodiment, A is selected from the group consisting of: phenyl,and heteroaryl, wherein phenyl and heteroaryl are unsubstituted orsubstituted with 1-4 substituents independently selected fromcyclopropyl. In another embodiment, A is selected from the groupconsisting of: phenyl, and heteroaryl, wherein phenyl and heteroaryl areunsubstituted or substituted with 1-4 substituents independentlyselected from CH₃. In another embodiment, A is selected from the groupconsisting of: phenyl, and heteroaryl, wherein phenyl and heteroaryl areunsubstituted or substituted with 1-4 substituents independentlyselected from F.

In another embodiment of the present invention, A is selected from thegroup consisting of: phenyl, pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, andpyridazine, wherein phenyl, pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, and pyridazineare unsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen.

In another embodiment of the present invention, A is selected from thegroup consisting of: phenyl, pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, andpyridazine, wherein phenyl, pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, and pyridazineare unsubstituted or substituted with 1-4 substituents independentlyselected from: cyclopropyl, CH₃, CH₂CH₃, —C(CH₃)₃, and F.

In another embodiment, A is selected from the group consisting of:phenyl, pyrazole, pyridine, thiophene, thiazole, and benzothiophene,wherein A is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen. Inanother embodiment, A is selected from the group consisting of: phenyl,pyrazole, pyridine, thiophene, thiazole, and benzothiophene, wherein Ais unsubstituted or substituted with 1-4 substituents independentlyselected from cyclopropyl, CH₃ and F.

In another embodiment, A is selected from the group consisting of:phenyl, pyrazole, pyridine, thiophene, thiazole, and benzothiophene,wherein A is unsubstituted or substituted with 1-4 substituentsindependently selected from cyclopropyl, CH₃ and F. In anotherembodiment, A is selected from the group consisting of: phenyl,pyrazole, pyridine, thiophene, thiazole, and benzothiophene, wherein Ais unsubstituted or substituted with 1-4 substituents independentlyselected from CH₃ and F.

In another embodiment, A is selected from the group consisting of:phenyl, pyridine, thiazole, and benzothiophene, wherein A isunsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl and halogen. In another embodiment, A isselected from the group consisting of phenyl, pyridine, thiazole, andbenzothiophene, wherein A is unsubstituted or substituted with 1-4substituents independently selected from cyclopropyl, CH₃ and F. Inanother embodiment, A is selected from the group consisting of phenyl,pyridine, thiazole, and benzothiophene, wherein A is unsubstituted orsubstituted with 1-4 substituents independently selected from CH₃ and F.

In another embodiment, A is aryl, wherein aryl is unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyl,C₃₋₆cycloalkyl and halogen. In another embodiment, A is aryl, whereinaryl is unsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl and halogen. In another embodiment, A is aryl.

In another embodiment, A is phenyl, wherein phenyl is unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyl,C₃₋₆cycloalkyl and halogen. In another embodiment, A is phenyl, whereinphenyl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl and halogen. In anotherembodiment, A is phenyl, wherein phenyl is unsubstituted or substitutedwith 1-4 substituents independently selected from CH₃ and F. In anotherembodiment, A is phenyl.

In another embodiment, A is heteroaryl, wherein heteroaryl isunsubstituted or substituted with 1-3 substituents independentlyselected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen. In anotherembodiment, A is heteroaryl, wherein heteroaryl is unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl,and halogen. In another embodiment, A is heteroaryl.

In another embodiment of the present invention, A is selected from thegroup consisting of pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, andpyridazine, wherein pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, and pyridazineare unsubstituted or substituted with 1-3 substituents independentlyselected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen.

In another embodiment of the present invention, A is selected from thegroup consisting of pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, andpyridazine, wherein pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, and pyridazineare unsubstituted or substituted with 1-3 substituents independentlyselected from: cyclopropyl, CH₃, CH₂CH₃, —C(CH₃)₃, and F. In anotherembodiment of the present invention, A is selected from the groupconsisting of: pyridine, thiophene, thiazole, benzothiophene, triazole,oxazole, pyrazine, thiadiazole, and pyridazine, wherein pyridine,thiophene, thiazole, benzothiophene, triazole, oxazole, pyrazine,thiadiazole, and pyridazine are unsubstituted or substituted with 1-3substituents independently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, andhalogen.

In another embodiment of the present invention, A is selected from thegroup consisting of: pyridine, thiophene, thiazole, benzothiophene,triazole, oxazole, pyrazine, thiadiazole, and pyridazine, whereinpyridine, thiophene, thiazole, benzothiophene, triazole, oxazole,pyrazine, thiadiazole, and pyridazine are unsubstituted or substitutedwith 1-3 substituents independently selected from: cyclopropyl, CH₃,CH₂CH₃, —C(CH₃)₃, and F.

In another embodiment of the present invention, A is selected from thegroup consisting of: pyrazole, thiophene, thiazole, benzothiophene,triazole, oxazole, pyrazine, thiadiazole, and pyridazine, whereinpyrazole, thiophene, thiazole, benzothiophene, triazole, oxazole,pyrazine, thiadiazole, and pyridazine are unsubstituted or substitutedwith 1-3 substituents independently selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, and halogen.

In another embodiment of the present invention, A is selected from thegroup consisting of: pyrazole, thiophene, thiazole, benzothiophene,triazole, oxazole, pyrazine, thiadiazole, and pyridazine, whereinpyrazole, thiophene, thiazole, benzothiophene, triazole, oxazole,pyrazine, thiadiazole, and pyridazine are unsubstituted or substitutedwith 1-3 substituents independently selected from: cyclopropyl, CH₃,CH₂CH₃, —C(CH₃)₃, and F.

In another embodiment of the present invention, A is selected from thegroup consisting of: thiophene, thiazole, benzothiophene, triazole,oxazole, pyrazine, thiadiazole, and pyridazine, wherein thiophene,thiazole, benzothiophene, triazole, oxazole, pyrazine, thiadiazole, andpyridazine are unsubstituted or substituted with 1-3 substituentsindependently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen.

In another embodiment of the present invention, A is selected from thegroup consisting of: thiophene, thiazole, benzothiophene, triazole,oxazole, pyrazine, thiadiazole, and pyridazine, wherein thiophene,thiazole, benzothiophene, triazole, oxazole, pyrazine, thiadiazole, andpyridazine are unsubstituted or substituted with 1-3 substituentsindependently selected from: cyclopropyl, CH₃, CH₂CH₃, —C(CH₃)₃, and F.

In another embodiment, A is selected from the group consisting of:pyrazole, pyridine, thiophene, thiazole, and benzothiophene, wherein Ais unsubstituted or substituted with 1-3 substituents independentlyselected from C₁₋₆alkyl and halogen. In another embodiment, A isselected from the group consisting of: pyrazole, pyridine, thiophene,thiazole, and benzothiophene, wherein A is unsubstituted or substitutedwith 1-3 substituents independently selected from CH₃ and F. In anotherembodiment, A is selected from the group consisting of: pyrazole,pyridine, thiophene, thiazole, and benzothiophene.

In another embodiment, A is selected from the group consisting of:pyrazole, thiazole, and benzothiophene, wherein A is unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyland halogen. In another embodiment, A is selected from the groupconsisting of: pyrazole, thiazole, and benzothiophene, wherein A isunsubstituted or substituted with 1-3 substituents independentlyselected from CH₃ and F. In another embodiment, A is selected from thegroup consisting of: pyrazole, thiazole, and benzothiophene.

In another embodiment, A is selected from the group consisting of:pyridine, thiazole, and benzothiophene, wherein A is unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyland halogen. In another embodiment, A is selected from the groupconsisting of: pyridine, thiazole, and benzothiophene, wherein A isunsubstituted or substituted with 1-3 substituents independentlyselected from CH₃ and F. In another embodiment, A is selected from thegroup consisting of: pyridine, thiazole, and benzothiophene.

In another embodiment, A is selected from the group consisting of:thiazole, and benzothiophene, wherein A is unsubstituted or substitutedwith 1-3 substituents independently selected from C₁₋₆alkyl and halogen.In another embodiment, A is selected from the group consisting of:thiazole, and benzothiophene, wherein A is unsubstituted or substitutedwith 1-3 substituents independently selected from CH₃ and F. In anotherembodiment, A is selected from the group consisting of: thiazole, andbenzothiophene.

In another embodiment, A is pyridine, wherein pyridine is unsubstitutedor substituted with 1-3 substituents independently selected fromC₁₋₆alkyl and halogen. In another embodiment, A is pyridine, whereinpyridine is unsubstituted or substituted with 1-3 substituentsindependently selected from CH₃ and F. In another embodiment, A ispyridine.

In another embodiment of the present invention, A is selected from thegroup consisting of: pyrazole, and pyridine, wherein pyrazole andpyridine are independently unsubstituted or substituted with 1-3substituents independently selected from C₁₋₆alkyl and halogen. Inanother embodiment of the present invention, A is selected from thegroup consisting of: pyrazole and pyridine. In another embodiment of thepresent invention, A is pyrazole. In another embodiment of the presentinvention, A is pyridine.

In another embodiment of the present invention, B is selected from thegroup consisting of: aryl, and heteroaryl, wherein aryl is unsubstitutedor substituted with 1-4 substituents independently selected fromC₁₋₆alkyl, halogen and CF₃, and wherein heteroaryl is unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl,halogen, and CF₃.

In another embodiment of the present invention, B is selected from thegroup consisting of: aryl, and heteroaryl, wherein aryl is unsubstitutedor substituted with 1-4 substituents independently selected fromC₁₋₆alkyl, and wherein heteroaryl is unsubstituted or substituted with1-3 substituents independently selected from C₁₋₆alkyl and halogen.

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, pyrazine, pyridine, and pyridazine, whereinphenyl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, halogen and CF₃, and whereinpyrazine, pyridine and pyridazine are unsubstituted or substituted with1-3 substituents independently selected from C₁₋₆alkyl, halogen, andCF₃. In another embodiment of the present invention, B is selected fromthe group consisting of: phenyl, pyrazine, pyridine, and pyridazine,wherein phenyl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, F, Cl, and CF₃, and whereinpyrazine, pyridine and pyridazine are unsubstituted or substituted with1-3 substituents independently selected from C₁₋₆alkyl, F, Cl, and CF₃.

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, and pyridine, wherein phenyl isunsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl, and wherein pyridine is unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyland halogen.

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, pyrazine, pyridine, and pyridazine, whereinphenyl is unsubstituted, and wherein pyrazine, pyridine and pyridazineare unsubstituted or substituted with 1-3 substituents independentlyselected from C₁₋₆alkyl, halogen, and CF₃. In another embodiment of thepresent invention, B is selected from the group consisting of: phenyl,pyrazine, pyridine, and pyridazine, wherein phenyl is unsubstituted, andwherein pyrazine, pyridine and pyridazine are unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl,F, Cl, and CF₃.

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, pyrazine, pyridine, and pyridazine, whereinpyrazine, pyridine and pyridazine are unsubstituted or substituted with1-3 substituents independently selected from C₁₋₆alkyl, halogen, andCF₃. In another embodiment of the present invention, B is selected fromthe group consisting of: phenyl, pyrazine, pyridine, and pyridazine,wherein pyrazine, pyridine and pyridazine are unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl,F, Cl, and CF₃

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, and pyridine, wherein phenyl isunsubstituted, and wherein pyridine is unsubstituted or substituted with1-3 substituents independently selected from C₁₋₆alkyl and halogen.

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, and pyridine, wherein pyridine isunsubstituted or substituted with 1-3 substituents independentlyselected from halogen.

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, and pyridine, wherein pyridine isunsubstituted or substituted with 1-3 substituents independentlyselected from C₁₋₆alkyl and F. In another embodiment of the presentinvention, B is selected from the group consisting of: phenyl, andpyridine, wherein pyridine is unsubstituted or substituted with 1-3substituents independently selected from F.

In another embodiment of the present invention, B is aryl, wherein arylis unsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl and halogen. In another embodiment of thepresent invention, B is aryl, wherein aryl is unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyland F. In another embodiment of the present invention, B is aryl,wherein aryl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl. In another embodiment of thepresent invention, B is aryl, wherein aryl is unsubstituted orsubstituted with 1-4 substituents independently selected from CH₃. Inanother embodiment of the present invention, B is aryl, wherein aryl isunsubstituted or substituted with 1-4 substituents independentlyselected from halogen. In another embodiment of the present invention, Bis aryl, wherein aryl is unsubstituted or substituted with 1-4substituents independently selected from F. In another embodiment of thepresent invention, B is aryl.

In another embodiment of the present invention, B is phenyl, whereinphenyl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl and halogen. In another embodimentof the present invention, B is phenyl, wherein phenyl is unsubstitutedor substituted with 1-4 substituents independently selected fromC₁₋₆alkyl and F. In another embodiment of the present invention, B isphenyl, wherein phenyl is unsubstituted or substituted with 1-4substituents independently selected from C₁₋₆alkyl. In anotherembodiment of the present invention, B is phenyl, wherein phenyl isunsubstituted or substituted with 1-4 substituents independentlyselected from CH₃. In another embodiment of the present invention, B isphenyl, wherein phenyl is unsubstituted or substituted with 1-4substituents independently selected from halogen. In another embodimentof the present invention, B is phenyl, wherein phenyl is unsubstitutedor substituted with 1-4 substituents independently selected from F. Inanother embodiment of the present invention, B is phenyl.

In another embodiment of the present invention, B is heteroaryl, whereinheteroaryl is unsubstituted or substituted with 1-3 substituentsindependently selected from C₁₋₆alkyl, halogen and CF₃.

In another embodiment of the present invention, B is heteroaryl, whereinheteroaryl is unsubstituted or substituted with one substituent selectedfrom C₁₋₆alkyl, halogen and CF₃.

In another embodiment of the present invention, B is pyridine, whereinpyridine is unsubstituted or substituted with 1-3 substituentsindependently selected from C₁₋₆alkyl, halogen and CF₃. In anotherembodiment of the present invention, B is pyridine, wherein pyridine isunsubstituted or substituted with one substituent selected fromC₁₋₆alkyl, halogen and CF₃.

In another embodiment of the present invention, B is pyridine, whereinpyridine is unsubstituted or substituted with 1-3 substituentsindependently selected from halogen. In another embodiment of thepresent invention, B is pyridine, wherein pyridine is unsubstituted orsubstituted with one substituent selected from halogen. In anotherembodiment of the present invention, B is pyridine, wherein pyridine isunsubstituted or substituted with 1-3 substituents independentlyselected from F. In another embodiment of the present invention, B ispyridine, wherein pyridine is unsubstituted or substituted with onesubstituent selected from F.

In another embodiment of the present invention, B is pyrazine, whereinpyrazine is unsubstituted or substituted with 1-3 substituentsindependently selected from C₁₋₆alkyl, halogen and CF₃. In anotherembodiment of the present invention, B is pyrazine, wherein pyrazine isunsubstituted or substituted with one substituent selected fromC₁₋₆alkyl, halogen and CF₃.

In another embodiment of the present invention, X is selected from thegroup consisting of: —NHSO₂CF₃, —NHSO₂CH₂CF₃, —NHSO₂CHF₂,—NHSO₂C₁₋₆alkyl, and —NHSO₂C₃₋₆cycloalkyl, wherein alkyl and cycloalkylare unsubstituted or substituted with 1-3 substituents independentlyselected from C₁₋₆alkyl. In another embodiment of the present invention,X is selected from the group consisting of: —NHSO₂CF₃, —NHSO₂CH₂CF₃,—NHSO₂CHF₂, —NHSO₂CH₃, and NHSO₂-cyclopropyl, wherein cyclopropyl areunsubstituted or substituted with 1-3 substituents independentlyselected from CH₃.

In another embodiment, X is selected from the group consisting of:—NHSO₂CF₃, —NHSO₂CH₂CF₃, —NHSO₂C₁₋₄alkyl, and —NHSO₂CHF₂.

In another embodiment of the present invention, X is selected from thegroup consisting of: —NHSO₂CF₃, —NHSO₂CH₂CF₃, —NHSO₂CH₃, and —NHSO₂CHF₂.

In another embodiment of the present invention, X is selected from thegroup consisting of: —NHSO₂CF₃, —NHSO₂CH₂CF₃, and —NHSO₂CHF₂. In anotherembodiment of the present invention, X is —NHSO₂CF₃.

In another embodiment of the present invention, X is selected from thegroup consisting of: —NHSO₂CH₂CF₃, —NHSO₂C₂₋₄alkyl, and —NHSO₂CHF₂.

In another embodiment of the present invention, X is selected from thegroup consisting of: —NHSO₂CH₂CF₃, and —NHSO₂C₂₋₄alkyl.

In another embodiment of the present invention, Z is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, and phenyl, wherein alkyl andphenyl are unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl.

In another embodiment of the present invention, Z is selected from thegroup consisting of: hydrogen, and phenyl, wherein phenyl isunsubstituted or substituted with 1-4 substituents independentlyselected from CH₃. In another embodiment of the present invention, Z isselected from the group consisting of: hydrogen, and phenyl, whereinphenyl is unsubstituted or substituted with one substituent selectedfrom CH₃.

In another embodiment of the present invention, Z is selected from thegroup consisting of: hydrogen, and phenyl, wherein phenyl isunsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl. In another embodiment of the present invention,Z is selected from the group consisting of: hydrogen, and phenyl,wherein phenyl is unsubstituted or substituted with 1-4 substituentsindependently selected from CH₃.

In another embodiment of the present invention, Z is C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl.

In another embodiment of the present invention, Z is hydrogen.

In another embodiment of the present invention, Z is phenyl, whereinphenyl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl. In another embodiment of thepresent invention, Z is phenyl, wherein phenyl is unsubstituted orsubstituted with 1-4 substituents independently selected from CH₃.

In another embodiment of the present invention, R^(a) is selected fromthe group consisting of: hydrogen, and C₁₋₆alkyl. In another embodimentof the present invention, R^(a) is selected from the group consistingof: hydrogen, and CH₃. In another embodiment of the present invention,R^(a) is hydrogen. In another embodiment of the present invention, R^(a)is CH₃.

In another embodiment of the present invention, R^(b) is selected fromthe group consisting of: hydrogen, and C₁₋₆alkyl. In another embodimentof the present invention, R^(b) is selected from the group consistingof: hydrogen, and CH₃. In another embodiment of the present invention,R^(b) is hydrogen. In another embodiment of the present invention, R^(b)is CH₃.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ia:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ib:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ic:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Id:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ie:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula If:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ig:

wherein the * bonds are trans bonds, or a pharmaceutically acceptablesalt thereof. In another embodiment of the present invention, theinvention relates to compounds of structural formula Ig wherein the *bonds are cis bonds, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ih:

wherein the * bonds are trans bonds, or a pharmaceutically acceptablesalt thereof. In another embodiment of the present invention, theinvention relates to compounds of structural formula Ih wherein the *bonds are cis bonds, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ii:

wherein the * bonds are trans bonds, or a pharmaceutically acceptablesalt thereof. In another embodiment of the present invention, theinvention relates to compounds of structural formula Ii wherein thebonds are cis bonds, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ij:

wherein the * bonds are trans bonds, or a pharmaceutically acceptablesalt thereof. In another embodiment of the present invention, theinvention relates to compounds of structural formula Ij wherein the *bonds are cis bonds, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ik:

wherein the * bonds are trans bonds, or a pharmaceutically acceptablesalt thereof. In another embodiment of the present invention, theinvention relates to compounds of structural formula Ik wherein the *bonds are cis bonds, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Il:

wherein the * bonds are trans bonds, or a pharmaceutically acceptablesalt thereof. In another embodiment of the present invention, theinvention relates to compounds of structural formula Il wherein the *bonds are cis bonds, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Im:

wherein the * bonds are trans bonds, or a pharmaceutically acceptablesalt thereof. In another embodiment of the present invention, theinvention relates to compounds of structural formula Im wherein the *bonds are cis bonds, or a pharmaceutically acceptable salt thereof.

The term “trans bonds” refers to bonds with the followingstereochemistry:

and pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, the compounds of structuralformula I have the following trans bond configuration:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the compound ofstructural formula I has the following trans bond configuration:

or a pharmaceutically acceptable salt thereof.

The term “cis bonds” refers to bonds with the following stereochemistry:

and pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, the compounds of structuralformula I have the following cis bond configuration:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the compound ofstructural formula I has the following cis bond configuration:

or a pharmaceutically acceptable salt thereof.

The compound of structural formula I includes the compounds ofstructural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im,In, Io, Ip, and Iq, and pharmaceutically acceptable salts, hydrates andsolvates thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I:

whereinA is selected from the group consisting of:

(1) phenyl, and

(2) heteroaryl,

wherein phenyl and heteroaryl are unsubstituted or substituted with 1-4substituents independently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, andhalogen;B is selected from the group consisting of:

(1) phenyl,

(2) pyrazine,

(3) pyridine, and

(4) pyridazine,

wherein pyrazine, pyridine and pyridazine are unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl,halogen, and CF₃;X is selected from the group consisting of

(1) —NHSO₂CF₃,

(2) —NHSO₂CH₂CF₃,

(3) —NHSO₂CHF₂,

(4) —NHSO₂C₁₋₆alkyl, and

(5) —NHSO₂C₃₋₆cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3substituents independently selected from C₁₋₆alkyl;Z is selected from the group consisting of

(1) hydrogen,

(2) C₁₋₆alkyl, and

(3) phenyl,

wherein alkyl and phenyl are unsubstituted or substituted with 1-4substituents independently selected from C₁₋₆alkyl; andR^(a) and R^(b) are independently selected from the group consisting of:hydrogen, and C₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds ofstructural Formula

whereinA is heteroaryl;B is phenyl;X is —NHSO₂CF₃;Z is hydrogen; andR^(a) and R^(b) are hydrogen;or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds of the presentinvention that are useful as antagonists of the leukotriene B₄ receptor1 (BLT1) are the following compounds:

-   (1)    N-(2-((3,4-Rac-cis)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (2)    N-(2-((3,4-Rac-trans)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (3)    N-(2-((3,4-Rac-cis)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (4)    N-(2-((3,4-Rac-trans)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (5)    1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-phenylthiophen-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (6)    N-(2-((3,4-Rac-trans)-3-((1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (7)    1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(pyridin-3-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (8)    1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-3-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (9)    1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiazol-5-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (10)    1,1,1-Trifluoro-N-(2-((3,4-rac-cis)-4-hydroxy-3-(thiazol-5-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (11)    1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-methylpyridin-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (12)    N-(2-((3,4-Rac-trans)-3-((1H-pyrazol-4-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (13)    1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((1-methyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (14)    1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (15)    1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(1,3-oxazol-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (16)    1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (17)    N-(2-{(rac-trans)-3-[(2-cyclopropyl-1,3-thiazol-4-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl)-1,1,1-trifluoromethanesulfonamide;-   (18)    1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(1-methyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (19)    1,1,1-Trifluoro-N-(2-{(rac-trans)-3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (20)    1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(6-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (21)    1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (22)    1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (23)    1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (24)    1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((2-phenylthiazol-4-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (25)    1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (26) 1,1,1-trifluoro-N-{2-[(3    S,4R)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (27)    1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (28)    1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(pyridazin-3-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methane-sulfonamide;-   (29)    1,1,1-Trifluoro-N-(2-((rac-trans)-3-((5-fluoropyridin-2-yl)methyl)-4-hydroxychroman-7-yl)phenyl)methanesulfonamide;-   (30)    N-(2-((3,4-Rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (31)    1,1,1-trifluoro-N-(2-(3,4-rac-cis)-4-hydroxy-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (32)    1,1,1-trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (33)    1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (34)    N-(2-((3,4-rac-trans)-3-(benzo[b]thiophen-2-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (35)    1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (36)    1,1,1-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (37)    1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (38)    1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (39)    (2-((3S,4R)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl)chroman-7-yl)phenyl)((trifluoromethyl)sulfonyl)amide;-   (40)    (2-((3R,4S)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl)chroman-7-yl)phenyl)((trifluoromethyl)sulfonyl)amide;-   (41)    1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((2-phenylthiazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (42)    1,1,1-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-((2-phenylthiazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (43)    1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-((2-phenylthiazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (44)    1,1,1-Trifluoro-N-(2-((3,4-trans)-3-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methyl)-4-hydroxychroman-7-yl)phenyl)methanesulfonamide;-   (45)    N-(2-((3,4-trans)-3-((2-(tert-butyl)thiazol-4-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (46)    N-(2-((3S,4R)-3-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (47)    N-(2-((3R,4S)-3-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;-   (48)    1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((1-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;-   (49)    (2-((3,4-trans)-4-hydroxy-3-((1-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)((trifluoromethyl)sulfonyl)amide;-   (50)    1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(1,3-thiazol-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;-   (51)    1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(1,3-thiazol-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;-   (52)    1,1,1-trifluoro-N-(2-{(3S,4R)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (53)    1,1,1-trifluoro-N-(2-{(3R,4S)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (54) 1,1,1-trifluoro-N-{2-[(3    S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;-   (55)    1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;-   (56)    1,1,1-Trifluoro-N-(2-{(3R,4S)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)-methanesulfonamide;-   (57)    1,1,1-Trifluoro-N-(2-{(3S,4R)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)-methanesulfonamide;-   (58)    N-{2-[(3R,4S)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;-   (59)    N-{2-[(3S,4R)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;-   (60)    1,1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (61)    1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (62) 1,1,1-trifluoro-N-{2-[(3    S,4R)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (63)    1,1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(6-methyl-pyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}-phenyl)methanesulfonamide;-   (64)    1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-((2-phenylthiazol-4-yl)-methyl)chroman-7-yl)-phenyl)methanesulfonamide;-   (65)    1,1,1-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-((2-phenylthiazol-4-yl)-methyl)chroman-7-yl)-phenyl)methanesulfonamide;-   (66)    1,1,1-trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(1-methyl-1H-pyrazol-5-yl)methyl]-3,4-di-hydro-2H-chromen-7-yl}-phenyl)methanesulfonamide;-   (67)    N-{2-[(3S,4R)-3-(biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;-   (68)    N-{2-[(3R,4S)-3-(biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;-   (69)    1,1,1-Trifluoro-N-(2-{(3,4-trans)-3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;-   (70)    1,1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)-methanesulfonamide;-   (71)    1,1,1-trifluoro-N-{2-[(3,4-trans)-4-hydroxy-3-(1H-pyrazol-3-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;-   (72)    N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (73)    N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;-   (74)    1,1,1-Trifluoro-N-(3-((3,4-rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyrazin-2-yl)methanesulfonamide;-   (75)    N-(2-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)-1-methylcyclopropane-1-sulfonamide;-   (76)    2,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyrazin-2-yl)ethanesulfonamide;-   (77)    2,2,2-Trifluoro-N-(3-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)ethanesulfonamide;-   (78)    2,2,2-Trifluoro-N-(3-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)ethanesulfonamide;-   (79)    2,2,2-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)ethanesulfonamide;-   (80)    2,2,2-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)ethanesulfonamide;-   (81)    1,1-Difluoro-N-(2-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (82)    1,1-Difluoro-N-(2-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (83)    1,1,1-Trifluoro-N-(4-fluoro-2-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;-   (84)    1,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;-   (85)    1,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;-   (86)    1,1-Difluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;-   (87)    1,1,1-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;-   (88)    2,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)-5-(trifluoromethyl)pyrazin-2-yl)ethanesulfonamide;-   (89)    N-(6-chloro-4-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide;-   (90)    N-(4-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoro-methanesulfonamide;-   (91)    N-(6-chloro-4-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide;-   (92)    1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide;    and-   (93)    1,1,1-trifluoro-N-(4-fluoro-2-(4-hydroxy-3-(1-(pyridin-2-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide;    and pharmaceutically acceptable salts thereof.

Although the specific stereochemistries described above are preferred,other stereoisomers, including diastereoisomers, enantiomers, epimers,and mixtures of these may also have utility in treating BLT1 mediateddiseases.

Synthetic methods for making the compounds are disclosed in the Examplesshown below. Where synthetic details are not provided in the examples,the compounds are readily made by a person of ordinary skill in the artof medicinal chemistry or synthetic organic chemistry by applying thesynthetic information provided herein.

Definitions

“Ac” is acetyl, which is CH₃C(═O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched, or combinations thereof, unless the carbonchain is defined otherwise. The term —C₂alkyl is ethyl. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. In oneembodiment of the present invention, alkyl is methyl.

“Cycloalkyl” means a saturated monocyclic, bicyclic or bridgedcarbocyclic ring, having a specified number of carbon atoms. Examples ofcycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,and the like. In one embodiment of the present invention, cycloalkyl iscyclopropyl.

“Aryl” means a monocyclic or bicyclic carbocyclic aromatic ring or ringsystem containing 5-14 carbon atoms, wherein at least one of the ringsis aromatic. Examples of aryl include phenyl and naphthyl. In oneembodiment of the present invention, aryl is phenyl.

“Heteroaryl” means monocyclic, or bicyclic ring or ring systemcontaining 3-14 carbon atoms and containing at least one ring heteroatomselected from N, NH, S (including SO and SO₂) and O, wherein at leastone of the heteroatom containing rings is aromatic. Examples ofheteroaryl include pyrazole, pyridine, thiophene, thiazole andbenzothiophene. In one embodiment, heteroaryl is pyrazole, pyridine,thiophene, thiazole and benzothiophene. In another embodiment,heteroaryl is pyridine. In another embodiment, heteroaryl is pyrazole,and pyridine. In another embodiment, heteroaryl is thiazole, In anotherembodiment, heteroaryl is pyrazole, pyridine, thiophene, thiazole,benzothiophene, triazole, oxazole, pyrazine, thiadiazole, andpyridazine. In another embodiment, heteroaryl is pyrazine, pyridine, andpyridazine.

“Halogen” includes fluorine, chlorine, bromine and iodine. In oneembodiment of the present invention, halogen is bromine, chlorine orfluorine. In another embodiment of the present invention, halogen ischlorine or fluorine. In another embodiment of the present invention,halogen is bromine. In another embodiment of the present invention,halogen is chlorine. In another embodiment of the present invention,halogen is fluorine.

“Me” represents methyl.

“Oxo” is ═O.

When any variable (e.g., R¹, R^(a), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. A squiggly line across abond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

Unless expressly depicted or described otherwise, substituents depictedin a structural formula with a “floating” bond, such as but not limitedto Z, are permitted on any available carbon atom in the ring to whichthe substituent is attached. In one embodiment of the present invention,Z may be substituted on any CH in the ring to which Z is attached.

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, salts and/or dosage formswhich are, using sound medical judgment, and following all applicablegovernment regulations, safe and suitable for administration to a humanbeing or an animal.

The term “% enantiomeric excess” (abbreviated “ee”) shall mean the %major enantiomer less the % minor enantiomer. Thus, a 70% enantiomericexcess corresponds to formation of 85% of one enantiomer and 15% of theother. The term “enantiomeric excess” is synonymous with the term“optical purity.”

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

The present invention encompasses all stereoisomeric forms of thecompounds of Formula I. Unless a specific stereochemistry is indicated,the present invention is meant to comprehend all such isomeric forms ofthese compounds. Centers of asymmetry that are present in the compoundsof Formula I can all independently of one another have (R) configurationor (S) configuration. When bonds to the chiral carbon are depicted asstraight lines in the structural Formulas of the invention, it isunderstood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. Similarly, when a compound name is recited without achiral designation for a chiral carbon, it is understood that both the(R) and (S) configurations of the chiral carbon, and hence individualenantiomers and mixtures thereof, are embraced by the name. Theproduction of specific stereoisomers or mixtures thereof may beidentified in the Examples where such stereoisomers or mixtures wereobtained, but this in no way limits the inclusion of all stereoisomersand mixtures thereof from being within the scope of this invention.

The invention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, enantiomers are asubject of the invention in enantiomerically pure form, both aslevorotatory and as dextrorotatory antipodes, in the form of racematesand in the form of mixtures of the two enantiomers in all ratios. In thecase of a cis/trans isomerism the invention includes both the cis formand the trans form as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, if desired,by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I or it can be done on a finalracemic product. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing astereogenic center of known configuration. Where compounds of thisinvention are capable of tautomerization, all individual tautomers aswell as mixtures thereof are included in the scope of this invention.Unless a particular isomer, salt, solvate (including hydrates) orsolvated salt of such racemate, enantiomer, diastereomer or tautomer isindicated, the present invention includes all such isomers, as well assalts, solvates (including hydrates) and solvated salts of suchracemates, enantiomers, diastereomers and tautomers and mixturesthereof.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

In the compounds of general formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H), deuterium (²H), and tritium (³H). Protium isthe predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Tritium is radioactive and may therefore provide for aradiolabeled compound, useful as a tracer in metabolic or kineticstudies. Isotopically-enriched compounds within structural formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

The independent syntheses of optical isomers and diastereoisomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well-known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Salts:

It will be understood that, as used herein, references to the compoundsof the present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate,and valerate. Furthermore, where the compounds of the invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereofinclude, but are not limited to, salts derived from inorganic basesincluding aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates, and in particular, the hydrates of the compounds of thepresent invention are included in the present invention as well.

Utilities The compounds of the present invention are potent antagonistsof the leukotriene B₄ receptor 1 (BLT1) receptor. The compounds, andpharmaceutically acceptable salts thereof, may be efficacious in thetreatment of diseases that are modulated by BLT1 ligands. Many of thesediseases are summarized below.

One or more of these diseases may be treated by the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, to a patient in need oftreatment. Also, the compounds of the present invention may be used forthe manufacture of a medicament which may be useful for treating one ormore of these diseases: (1) non-insulin dependent diabetes mellitus(Type 2 diabetes); (2) obesity; (3) hypertension; (4) dyslipidemia andlipid disorders; (5) cancer; (6) Metabolic Syndrome; (7) myocardialinfarction; (8) stroke; (9) insulin resistance; (10) hyperglycemia; (11)Non-alcoholic fatty liver disease/nonalcoholic steatohepatitis; and (12)atherosclerosis.

Preferred uses of the compounds may be for the treatment of one or moreof the following diseases by administering a therapeutically effectiveamount to a patient in need of treatment. The compounds may be used formanufacturing a medicament for the treatment of one or more of thesediseases: (1) Type 2 diabetes, and specifically hyperglycemia associatedwith Type 2 diabetes; (2) Metabolic Syndrome; (3) obesity; and (4)hypercholesterolemia.

The compounds may be effective in lowering glucose and lipids indiabetic patients and in non-diabetic patients who have impaired glucosetolerance and/or are in a pre-diabetic condition. The compounds mayameliorate hyperinsulinemia, which often occurs in diabetic orpre-diabetic patients, by modulating the swings in the level of serumglucose that often occurs in these patients. The compounds may also beeffective in treating or reducing insulin resistance. The compounds maybe effective in treating or preventing gestational diabetes.

The compounds may also be effective in treating or preventing lipiddisorders. The compounds may be effective in treating or preventingdiabetes related disorders. The compounds may also be effective intreating or preventing obesity related disorders.

The invention also includes pharmaceutically acceptable salts of thecompounds, and pharmaceutical compositions comprising the compounds anda pharmaceutically acceptable carrier. The compounds may be useful intreating insulin resistance, Type 2 diabetes, hyperglycemia, anddyslipidemia that is associated with Type 2 diabetes and insulinresistance.

The compounds may also be useful for the treatment of obesity A compoundof the present invention, or a pharmaceutically acceptable salt thereof,may be used in the manufacture of a medicament for the treatment of Type2 diabetes in a human or other mammalian patient.

A method of treating Type 2 diabetes comprises the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound, to a human or other mammaliansubject or patient in need of treatment. Other medical uses of thecompounds of the present invention are described herein.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type 1 diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type 2 diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type 2 diabetics are also obese. The compositions of thepresent invention may be useful for treating both Type 1 and Type 2diabetes. The term “diabetes associated with obesity” refers to diabetescaused by obesity or resulting from obesity.

Diabetes is characterized by a fasting plasma glucose level of greaterthan or equal to 126 mg/dl. A diabetic subject has a fasting plasmaglucose level of greater than or equal to 126 mg/dl. A pre diabeticsubject is someone suffering from prediabetes. Prediabetes ischaracterized by an impaired fasting plasma glucose (FPG) level ofgreater than or equal to 110 mg/dl and less than 126 mg/dl; or impairedglucose tolerance; or insulin resistance. A prediabetic subject is asubject with impaired fasting glucose (a fasting plasma glucose (FPG)level of greater than or equal to 110 mg/dl and less than 126 mg/dl); orimpaired glucose tolerance (a 2 hour plasma glucose level of >140 mg/dland <200 mg/dl); or insulin resistance, resulting in an increased riskof developing diabetes.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat a diabeticsubject. One outcome of treatment may be decreasing the glucose level ina subject with elevated glucose levels. Another outcome of treatment maybe decreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentis decreasing LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome oftreatment is increasing insulin sensivity. Another outcome of treatmentmay be enhancing glucose tolerance in a subject with glucoseintolerance. Yet another outcome of treatment may be decreasing insulinresistance in a subject with increased insulin resistance or elevatedlevels of insulin. Prevention of diabetes mellitus, in particulardiabetes associated with obesity, refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject in need thereof. A subject in need of preventingdiabetes is a prediabetic subject that is overweight or obese.

The term “diabetes related disorders” should be understood to meandisorders that are associated with, caused by, or result from diabetes.Examples of diabetes related disorders include retinal damage, kidneydisease, and nerve damage.

The term “atherosclerosis” as used herein encompasses vascular diseasesand conditions that are recognized and understood by physicianspracticing in the relevant fields of medicine. Atheroscleroticcardiovascular disease, coronary heart disease (also known as coronaryartery disease or ischemic heart disease), cerebrovascular disease andperipheral vessel disease are all clinical manifestations ofatherosclerosis and are therefore encompassed by the terms“atherosclerosis” and “atherosclerotic disease.” The combinationcomprised of a therapeutically effective amount of a BLT1 antagonist incombination with a therapeutically effective amount of ananti-hypertensive agent may be administered to prevent or reduce therisk of occurrence, or recurrence where the potential exists, of acoronary heart disease event, a cerebrovascular event, or intermittentclaudication. Coronary heart disease events are intended to include CHDdeath, myocardial infarction (i.e., a heart attack), and coronaryrevascularization procedures. Cerebrovascular events are intended toinclude ischemic or hemorrhagic stroke (also known as cerebrovascularaccidents) and transient ischemic attacks. Intermittent claudication isa clinical manifestation of peripheral vessel disease. The term“atherosclerotic disease event” as used herein is intended to encompasscoronary heart disease events, cerebrovascular events, and intermittentclaudication. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease events arethose for whom the potential for recurrence of such an event exists. Theterm “atherosclerosis related disorders” should be understood to meandisorders associated with, caused by, or resulting from atherosclerosis.

The term “hypertension” as used herein includes essential, or primary,hypertension wherein the cause is not known or where hypertension is dueto greater than one cause, such as changes in both the heart and bloodvessels; and secondary hypertension wherein the cause is known. Causesof secondary hypertension include, but are not limited to obesity;kidney disease; hormonal disorders; use of certain drugs, such as oralcontraceptives, corticosteroids, cyclosporin, and the like. The term“hypertension” encompasses high blood pressure, in which both thesystolic and diastolic pressure levels are elevated (>140 mmHg/>90mmHg), and isolated systolic hypertension, in which only the systolicpressure is elevated to greater than or equal to 140 mm Hg, while thediastolic pressure is less than 90 mm Hg. Normal blood pressure may bedefined as less than 120 mmHg systolic and less than 80 mmHg diastolic.A hypertensive subject is a subject with hypertension. Apre-hypertensive subject is a subject with a blood pressure that isbetween 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg. One outcome oftreatment is decreasing blood pressure in a subject with high bloodpressure. Treatment of hypertension refers to the administration of thecompounds and combinations of the present invention to treathypertension in a hypertensive subject. Treatment ofhypertension-related disorder refers to the administration of a compoundor combination of the present invention to treat thehypertension-related disorder. Prevention of hypertension, or ahypertension related disorder, refers to the administration of thecombinations of the present invention to a pre-hypertensive subject toprevent the onset of hypertension or a hypertension related disorder.The hypertension-related disorders herein are associated with, causedby, or result from hypertension. Examples of hypertension-relateddisorders include, but are not limited to: heart disease, heart failure,heart attack, kidney failure, and stroke.

Dyslipidemias and lipid disorders are disorders of lipid metabolismincluding various conditions characterized by abnormal concentrations ofone or more lipids (i.e., cholesterol and triglycerides), and/orapolipoproteins (i.e., apolipoproteins A, B, C and E), and/orlipoproteins (i.e., the macromolecular complexes formed by the lipid andthe apolipoprotein that allow lipids to circulate in blood, such as LDL,VLDL and IDL). Hyperlipidemia is associated with abnormally high levelsof lipids, LDL and VLDL cholesterol, and/or triglycerides. Treatment ofdyslipidemia refers to the administration of the combinations of thepresent invention to a dyslipidemic subject. Prevention of dyslipidemiarefers to the administration of the combinations of the presentinvention to a pre-dyslipidemic subject. A pre-dyslipidemic subject is asubject with higher than normal lipid levels, that is not yetdyslipidemic.

The terms “dyslipidemia related disorders” and “lipid disorder relateddisorders” should be understood to mean disorders associated with,caused by, or resulting from dyslipidemia or lipid disorders. Examplesof dylipidemia related disorder and lipid disorder related disordersinclude, but are not limited to: hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low high density lipoprotein (HDL) levels, highplasma low density lipoprotein (LDL) levels, atherosclerosis and itssequelae, coronary artery or carotid artery disease, heart attack, andstroke.

The term “obesity” as used herein is a condition in which there is anexcess of body fat. The operational definition of obesity is based onthe Body Mass Index (BMI), which is calculated as body weight per heightin meters squared (kg/m²). “Obesity” refers to a condition whereby anotherwise healthy subject has a Body Mass Index (BMI) greater than orequal to 30 kg/m², or a condition whereby a subject with at least oneco-morbidity has a BMI greater than or equal to 27 kg/m². An “obesesubject” is an otherwise healthy subject with a Body Mass Index (BMI)greater than or equal to 30 kg/m² or a subject with at least oneco-morbidity with a BMI greater than or equal to 27 kg/m². An overweightsubject is a subject at risk of obesity. A “subject at risk of obesity”is an otherwise healthy subject with a BMI of 25 kg/m² to less thankg/m² or a subject with at least one co-morbidity with a BMI of 25 kg/m²to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes mellitus, non-insulin dependent diabetesmellitus—type 2, diabetes associated with obesity, impaired glucosetolerance, impaired fasting glucose, insulin resistance syndrome,dyslipidemia, hypertension, hypertension associated with obesity,hyperuricacidemia, gout, coronary artery disease, myocardial infarction,angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fattyliver; cerebral infarction, cerebral thrombosis, transient ischemicattack, orthopedic disorders, arthritis deformans, lumbodynia,emmeniopathy, and infertility. In particular, co-morbidities include:hypertension, hyperlipidemia, dyslipidemia, glucose intolerance,cardiovascular disease, sleep apnea, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds of the present invention. Another outcome of treatment may bepreventing body weight regain of body weight previously lost as a resultof diet, exercise, or pharmacotherapy. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. The treatment may suitably result in a reduction in food orcalorie intake by the subject, including a reduction in total foodintake, or a reduction of intake of specific components of the diet suchas carbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds of the present invention. Anotheroutcome of prevention may be preventing body weight regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subj ects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovariandisease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating and bulimia, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. Further examples of obesity-related disordersare metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, sexual and reproductive dysfunction, such as infertility,hypogonadism in males and hirsutism in females, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), cardiovascular disorders, inflammation, such assystemic inflammation of the vasculature, arteriosclerosis,hypercholesterolemia, hyperuricaemia, lower back pain, gallbladderdisease, gout, and kidney cancer. The compounds of the present inventionare also useful for reducing the risk of secondary outcomes of obesity,such as reducing the risk of left ventricular hypertrophy.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (Adult Treatment Panel III, or ATP III), National Institutesof Health, 2001, NIH Publication No. 01-3670. E. S. Ford et al., JAMA,vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined ashaving metabolic syndrome if the person has three or more of thefollowing disorders: abdominal obesity, hypertriglyceridemia, low HDLcholesterol, high blood pressure, and high fasting plasma glucose. Thecriteria for these are defined in ATP-III. Treatment of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with metabolic syndrome. Prevention of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with two of the disorders that define metabolicsyndrome. A subject with two of the disorders that define metabolicsyndrome is a subject that has developed two of the disorders thatdefine metabolic syndrome, but has not yet developed three or more ofthe disorders that define metabolic syndrome.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to a human or other mammal in need oftreatment.

The term “patient” should be understood to mean a human or other mammalin need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringa therapeutically effective amount of the compound of structural formulaI to the mammal (human or other mammal) in need of such treatment orprophylaxis. The need for a prophylactic administration according to themethods of the present invention is determined via the use of well knownrisk factors. The therapeutically effective amount of an individualcompound is determined, in the final analysis, by the physician orveterinarian in charge of the case, but depends on factors such as theexact disease to be treated, the severity of the disease and otherdiseases or conditions from which the patient suffers, the chosen routeof administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with a therapeutically effective dose of acompound of the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.Preferably compounds of the present invention are administered orally.

In the treatment or prevention of conditions which require antagonism ofBLT1 receptor activity, an appropriate dosage level will generally beabout 0.01 to 500 mg per kg patient body weight per day which may beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions maypreferably be provided in the form of tablets containing 1.0 to 1000 mgof the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0,50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0,750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention may be indicated, generally satisfactory results couldbe obtained when the compounds of the present invention are administeredat a daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the patient undergoing therapy.

The compounds of this invention may be used in pharmaceuticalcompositions comprising (a) the compound(s) or a pharmaceuticallyacceptable salt thereof, and (b) a pharmaceutically acceptable carrier.The compounds of this invention may be used in pharmaceuticalcompositions that include one or more other active pharmaceuticalingredients. The compounds of this invention may also be used inpharmaceutical compositions in which the compound of the presentinvention or a pharmaceutically acceptable salt thereof is the onlyactive ingredient.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients.

Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

Combination Therapy

The compounds of the present invention may be useful in methods for theprevention or treatment of the aforementioned diseases, disorders andconditions in combination with other therapeutic agents.

The compounds of the present invention may be useful in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of formula Ior the other drugs may have utility, where the combination of the drugstogether are safer, more effective or more therapeutically effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefore, contemporaneously orsequentially with a compound of formula I. When a compound of formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of formula I.

Examples of other active ingredients that may be administered separatelyor in the same pharmaceutical composition in combination with a compoundof the formulas described herein include, but are not limited to: (1)dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin,omarigliptin, trelagliptin, teneligliptin, bisegliptin, anagliptin,vildagliptin, saxagliptin, alogliptin, melogliptin, linagliptin,gosogliptin, evogliptin, and gemigliptin), (2) insulin sensitizers,including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone,AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone,and balaglitazone), and other PPAR ligands, including (1) PPARu/y dualagonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar,aleglitazar, sodelglitazar, and naveglitazar); (2) PPARU agonists suchas fenofibric acid derivatives (e.g., gemfibrozil, clofibrate,ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARy modulators(SPPARyM's), (e.g., such as those disclosed in WO 02/060388, WO02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO2004/066963); and (4) PPARy partial agonists; (ii) biguanides, such asmetformin and its pharmaceutically acceptable salts, in particular,metformin hydrochloride, and extended-release formulations thereof, suchas Glumetza™, Fortamet™, and GlucophageXR™; and (iii) protein tyrosinephosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); (3)insulin or insulin analogs (e.g., insulin detemir, insulin glulisine,insulin degludec, insulin glargine, insulin lispro and inhalableformulations of each); (4) leptin and leptin derivatives and agonists;(5) amylin and amylin analogs (e.g., pramlintide); (6) sulfonylurea andnon-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide,glipizide, glimepiride, mitiglinide, meglitinides, nateglinide andrepaglinide); (7) α-glucosidase inhibitors (e.g., acarbose, vogliboseand miglitol); (8) glucagon receptor antagonists (e.g., MK-3577,MK-0893, LY-2409021 and KT6-971); (9) incretin mimetics, such as GLP-1,GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists(e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide,lixisenatide, taspoglutide, CJC-1131, and BIM-51077, includingintranasal, transdermal, and once-weekly formulations thereof); (10) LDLcholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(e.g., simvastatin, lovastatin, pravastatin, crivastatin, fluvastatin,atorvastatin, pitavastatin and rosuvastatin), (ii) bile acidsequestering agents (e.g., colestilan, colestimide, colesevalamhydrochloride, colestipol, cholestyramine, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) inhibitors of cholesterolabsorption, (e.g., ezetimibe), and (iv) acyl CoA:cholesterolacyltransferase inhibitors, (e.g., avasimibe); (11) HDL-raising drugs,(e.g., niacin and nicotinic acid receptor agonists, and extended-releaseversions thereof; (12) antiobesity compounds; (13) agents intended foruse in inflammatory conditions, such as aspirin, non-steroidalanti-inflammatory drugs or NSAIDs, glucocorticoids, and selectivecyclooxygenase-2 or COX-2 inhibitors; (14) antihypertensive agents, suchas ACE inhibitors (e.g., lisinopril, enalapril, ramipril, captopril,quinapril, and tandolapril), A-II receptor blockers (e.g., losartan,candesartan, irbesartan, olmesartan, medoxomil, valsartan, telmisartan,and eprosartan), renin inhibitors (e.g., aliskiren), beta blockers, andcalcium channel blockers; (15) glucokinase activators (GKAs) (e.g.,AZD6370); (16) inhibitors of 11β-hydroxysteroid dehydrogenase type 1;(17) CETP inhibitors (e.g., anacetrapib, evacetrapib, torcetrapib, andAT-03); (18) inhibitors of fructose 1,6-bisphosphatase; (19) inhibitorsof acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); (20) AMP-activatedProtein Kinase (AMPK) activators (e.g., MB-11055); (21) other agonistsof the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g.,MBX2982 and PSN821), (iii) GPR-40 (e.g., fasiglifam, JTT-851, TAK-875,and P-11187, and (iv) GPR-120 (e.g., KDT-501); (22) SSTR3 antagonists(e.g., pasireotide, and such as those disclosed in WO 2009/011836); (23)neuromedin U receptor agonists (e.g., such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS)); (24)SCD inhibitors; (25) GPR-105 antagonists (e.g., such as those disclosedin WO 2009/000087); (26) SGLT inhibitors (e.g., LIK-066, ASP1941,SGLT-3, ertugliflozin, empagliflozin, dapagliflozin, canagliflozin,BI-10773, PF-04971729, remogloflozin, luseogliflozin, tofogliflozin,ipragliflozin, and LX-4211); (27) inhibitors of (i) acyl coenzymeA:diacylglycerol acyltransferase 1, DGAT-1 (e.g., pradigastat, andP-7435) and acyl coenzyme A:diacylglycerol acyltransferase 2, DGAT-2;(28) inhibitors of fatty acid synthase; (29) inhibitors of acyl coenzymeA:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); (30)agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19,GPR131, and M-BAR) (eg., sodium taurocholate); (31) ileal bile acidtransporter inhibitors (eg., elobixibat); (32) PACAP, PACAP mimetics,and PACAP receptor 3 agonists; (33) PPAR agonists; (34) protein tyrosinephosphatase-1B (PTP-1B) inhibitors; (35) IL-lb antibodies andinhibitors, (e.g., gevokizumab, canakinumab, danazol, AC-201, andBLX-1002); and (36) bromocriptine mesylate and rapid-releaseformulations thereof.

Of particular interest are dipeptidyl peptidase-IV (DPP-4) inhibitorsthat may be useful in combination with compounds of the presentinvention. Such inhibitors include, without limitation, sitagliptin(disclosed in U.S. Pat. No. 6,699,871), omarigliptin, trelagliptin,teneligliptin, bisegliptin, anagliptin, LC15-0444, vildagliptin,saxagliptin, alogliptin, melogliptin, linagliptin, gosogliptin,evogliptin, gemigliptin, and pharmaceutically acceptable salts thereof,and fixed-dose combinations of these compounds with metforminhydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin,rosuvastatin, or a sulfonylurea.

GPR-40 agonists that may be useful in combination with compounds of theformulas described herein include, but are not limited to: (1)5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2-methylpyridine-3-yl]-2,3-dihydro-1H-indene-1-yl]oxy]phenyl]isothiazole-3-ol1-oxide; (2)5-(4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)-methoxy)-phenyl)isothiazole-3-ol1-oxide; and (3)5-(4-((3-(2-methyl-6-(3-hydroxypropoxy)-pyridine-3-yl)-2-methylphenyl)methoxy)-phenyl)isothiazole-3-ol1-oxide; and (4)5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]-methoxy]phenyl]isothiazole-3-ol1-oxide, and pharmaceutically acceptable salts thereof.

Antiobesity compounds that may be combined with compounds of formula Iinclude topiramate; zonisamide; naltrexone; phentermine; bupropion; thecombination of bupropion and naltrexone; the combination of bupropionand zonisamide; the combination of topiramate and phentermine;fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such asorlistat and cetilistat; melanocortin receptor agonists, in particular,melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentratinghormone (MCH) receptor antagonists; neuropeptide Y1 or Y5 antagonists(such as MK-0557); β₃ adrenergic receptor agonists; CB-1 receptorinverse agonists and antagonists; ghrelin antagonists; bombesin receptoragonists (such as bombesin receptor subtype-3 agonists); and5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For areview of anti-obesity compounds that may be useful in combination witha compound of the present invention, see S. Chaki et al., “Recentadvances in feeding suppressing agents: potential therapeutic strategyfor the treatment of obesity,” Expert Opin. Ther. Patents, 11: 1677-1692(2001); D. Spanswick and K. Lee, “Emerging antiobesity drugs,” ExpertOpin. Emerging Drugs, 8: 217-237 (2003); J. A. Fernandez-Lopez, et al.,“Pharmacological Approaches for the Treatment of Obesity,” Drugs, 62:915-944 (2002); and K. M. Gadde, et al., “Combination pharmaceuticaltherapies for obesity,” Exp. Opin. Pharmacother., 10: 921-925 (2009).

Glucagon receptor antagonists that may be useful in combination with thecompounds of formula I include, but are not limited to: (1)N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine;(2)N-[4-((1R)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-(3-alanine;(3)N-(4-{1-[3-(2,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-3-alanine;(4)N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-3-alanine;(5)N-(4-{(1S)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3-yl)methyl]butyl}benzoyl)-β-alanine;and (6)N-(4-{(1S)-1-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}benzoyl)-3-alanine;and pharmaceutically acceptable salts thereof.

Another embodiment of the present invention relates to a pharmaceuticalcomposition comprising one or more of the following agents: (a) acompound of structural formula I; (b) one or more compounds selectedfrom the group consisting of: (1) dipeptidyl peptidase-IV (DPP-4)inhibitors (e.g., sitagliptin, omarigliptin, trelagliptin,teneligliptin, bisegliptin, anagliptin, vildagliptin, saxagliptin,alogliptin, melogliptin, linagliptin, gosogliptin, evogliptin, andgemigliptin); (2) insulin sensitizers, including (i) PPARy agonists,such as the glitazones (e.g. AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, pioglitazone, rosiglitazone, and balaglitazone)and other PPAR ligands, including (1) PPARa/y dual agonists, such asZYH1, YYH2, chiglitazar, GFT505, muraglitazar, aleglitazar,sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibricacid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate,fenofibrate and bezafibrate), (3) selective PPARy modulators(SPPARyM's), (4) PPARy partial agonists; (ii) biguanides, such asmetformin and its pharmaceutically acceptable salts, in particular,metformin hydrochloride, and extended-release formulations thereof, suchas Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosinephosphatase-1B (PTP-1B) inhibitors, such as ISI-113715, and TTP814; (3)sulfonylurea and non-sulfonylurea insulin secretagogues, (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, andmeglitinides, such as nateglinide and repaglinide); (4) α-glucosidaseinhibitors (e.g., acarbose, voglibose and miglitol)(5) glucagon receptorantagonists; (6) LDL cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (e.g., lovastatin, simvastatin, pravastatin,cerivastatin, fluvastatin, atorvastatin, pitavastatin, androsuvastatin), (ii) bile acid sequestering agents (e.g., colestilan,cholestyramine, colestimide, colesevelam hydrochloride, colestipol, anddialkylaminoalkyl derivatives of a cross-linked dextran), (iii)inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acylCoA:cholesterol acyltransferase inhibitors (e.g., avasimibe); (7)HDL-raising drugs, such as niacin or a salt thereof and extended-releaseversions thereof; and nicotinic acid receptor agonists; (8) antiobesitycompounds; (9) agents intended for use in inflammatory conditions, suchas aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors; (10)antihypertensive agents, such as ACE inhibitors (e.g., enalapril,lisinopril, ramipril, captopril, quinapril, and tandolapril), A-IIreceptor blockers (e.g., losartan, candesartan, irbesartan, olmesartanmedoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors(e.g., aliskiren), beta blockers (e.g., calcium channel blockers); (11)glucokinase activators (GKAs) (e.g., AZD6370, GKM-001, TMG-123,HMS-5552, DS-7309, PF-04937319, TTP-399, ZYGK-1); (12) inhibitors of11β-hydroxysteroid dehydrogenase type 1; (13) inhibitors of cholesterylester transfer protein (CETP), (e.g., torcetrapib, evacetrapib,anacetrapib, and AT-03); (14) inhibitors of fructose 1,6-bisphosphatase(e.g., MB-07803, and such as those disclosed in U.S. Pat. Nos.6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); (15)inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); (16)AMP-activated Protein Kinase (AMPK) activators (e.g., MB-11055); (17)agonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119(e.g., MBX2982, and PSN821), (iii) GPR-40 (e.g., fasiglifam, JTT-851,P-11187, and (iv) GPR-120 (e.g., KDT-501); (18) SSTR3 antagonists (e.g.,pasireotide, and such as those disclosed in WO 2009/011836); (19)neuromedin U receptor agonists (e.g., such as those disclosed inWO2009/042053, including, but not limited to, neuromedin S (NMS)); (20)inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD); (21) GPR-105antagonists (e.g., such as those disclosed in WO 2009/000087); (22)inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT)inhibitors and its various isoforms, such as SGLT-1; SGLT-2 (e.g.,LIK-066, ertuglifozin, ASP1941, luseogliflozin, BI10773, tofogliflozin,LX4211, canagliflozin, dapagliflozin, remogliflozin, and ipragliflozin;and SGLT-3); (23) inhibitors of (i) acyl coenzyme A:diacylglycerolacyltransferase 1, DGAT-1 (e.g., pradigastat, and P-7435) and acylcoenzyme A:diacylglycerol acyltransferase 2, DGAT-2; (24) inhibitors offatty acid synthase; (25) inhibitors of acyl coenzyme A:monoacylglycerolacyltransferase 1 and 2 (MGAT-1 and MGAT-2); (26) agonists of the TGR5receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR) (eg.,sodium taurocholate); (28) bromocriptine mesylate and rapid-releaseformulations thereof, and (29) IL-lb antibodies and inhibitors (e.g.,gevokizumab, canakinumab, danazol, AC-201, and BLX-1002); and (c) apharmaceutically acceptable carrier.

Specific compounds that may be useful in combination with a compound ofthe present invention include: simvastatin, mevastatin, ezetimibe,atorvastatin, rosuvastatin, sitagliptin, omarigliptin, metformin,sibutramine, orlistat, topiramate, naltrexone, bupriopion, phentermine,losartan, losartan with hydrochlorothiazide, olmesartan, canagliflozin,dapagliflozin, ipragliflozin and ertugliflozin.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds with two or more active compounds selected from biguanides,sulfonylureas, HMG-CoA reductase inhibitors, PPARy agonists, DPP-4inhibitors, anti-obesity compounds, and anti-hypertensive agents.

The present invention may also provide a method for the treatment orprevention of a leukotriene B₄ receptor 1 (BLT1) mediated disease, whichmethod comprises administration to a patient in need of such treatmentor at risk of developing a BLT1 mediated disease of an amount of a BLT1antagonist and an amount of one or more active ingredients, such thattogether they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a BLT1 antagonist and one or moreactive ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a BLT1 antagonist and one or more active ingredientsfor the manufacture of a medicament for the treatment or prevention of aBLT1 mediated disease. In a further or alternative aspect of the presentinvention, there is therefore provided a product comprising a BLT1antagonist and one or more active ingredients as a combined preparationfor simultaneous, separate or sequential use in the treatment orprevention of a BLT1 mediated disease. Such a combined preparation maybe, for example, in the form of a twin pack.

For the treatment or prevention of diabetes, obesity, hypertension,Metabolic Syndrome, dyslipidemia, cancer, atherosclerosis, and relateddisorders thereof, a compound of the present invention may be used inconj unction with another pharmaceutical agent effective to treat thatdisorder.

The present invention may also provide a method for the treatment orprevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an effective amount of a compound of the present invention andan amount of another pharmaceutical agent effective to threat thatdisorder, such that together they give effective relief.

The present invention may also provide a method for the treatment orprevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent useful in treating that particularcondition, such that together they give effective relief.

The term “therapeutically effective amount” or “a therapeuticallyeffective dose” means the amount the compound of structural formula Ithat will elicit the biological or medical response of a tissue, system,animal, mammal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician, which includesalleviation of the symptoms of the disorder being treated. The novelmethods of treatment of this invention are for disorders known to thoseskilled in the art. The term “mammal” includes, but is not limited to,humans, and companion animals such as dogs and cats.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, a therapeutically effective dose of each will beused. Thus, for example, when a compound of the Formula I is combinedwith a DPIV inhibitor the weight ratio of the compound of the Formula Ito the DPIV inhibitor will generally range from about 1000:1 to about1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the Formula I and other active ingredients will generallyalso be within the aforementioned range, but in each case, an effectivedose of each active ingredient should be used.

Methods of Synthesis of the Compounds of the Present Invention: Thefollowing reaction schemes and Examples illustrate methods which may beemployed for the synthesis of the compounds of structural formula Idescribed in this invention. Those skilled in the art will readilyunderstand that known variations of protecting groups, as well as of theconditions and processes of the following preparative procedures, can beused to prepare these compounds. It is also understood that whenever achemical reagent such as a boronic acid or a boronate is notcommercially available, such a chemical reagent can be readily preparedfollowing one of numerous methods described in the literature. Alltemperatures are degrees Celsius unless otherwise noted. Mass spectra(MS) were measured either by electrospray ion-mass spectroscopy (ESMS)or by atmospheric pressure chemical ionization mass spectroscopy (APCI).All temperatures are degrees Celsius unless otherwise noted.

List of Abbreviations 3,4-cis means 3S,4S or 3R,4R; 3,4-trans means3S,4R or 3R,4S; Racemic trans or trans racemic or Rac-trans or rac-transmeans a mixture of 3S,4R and 3R,4S; Racemic cis or cis racemic orRac-cis or rac-cis means a mixture of 3S,4S and 3R,4R; Ac is acetyl;AcCN is acetonitrile; Ac₂O is acetic anhydride; Alk is alkyl; anh. isanhydrous; aq or aq. is aqueous; Ar is aryl; atm is atmosphere; Boc istert-butoxycarbonyl; Bn-O is phenyl-CH₂—O or benzyloxy; n-BuLi isn-butyl lithium; t-BuOK is potassium tert-butoxide; ° C. is degreescelsius; calcd. is calculated; Cbz is benzyloxycarbonyl; Celite™ isdiatomaceous earth; CH₂Cl₂ is dichloromethane; CISO₂Me ismethanesulfonyl chloride; conc or conc. is concentrated; CPME iscyclopropyl methyl ether; CV is column volumes; DCM is dichloromethane;DEA is diethyl amine; DIPEA is N,N-diisopropylethylamine; DIPA isdiisopropyl amine; DMAP is 4-dimethyl-aminopyridine; DMF isN,N-dimethylformamide; DMS is dimethyl sulfide; DMSO isdimethylsulfoxide; eq or equiv is equivalent(s); EA or EtOAc is ethylacetate; Et is ethyl; Et₃N is triethyl amine; Et₂O is diethyl ether;EtMgBr is ethyl magnesium bromide; EtOH is ethanol; g is gram(s); h orhr or hrs is hour(s); hex is hexanes; HPLC is high pressure liquidchromatography; HOAc or AcOH is acetic acid; kg is kilogram(s); IPA isisopropanol; KOAc is potassium acetate; KOtBu is potassiumtert-butoxide; KHMDS is potassium hexamethyl disilazide; L is liter; LAHis lithium aluminum hydride; M is molar; LC-MS, LCMS or LC/MS is liquidchromatography-mass spectroscopy; LDA is lithium diisopropyl amide; Meis methyl; MeO is methoxy; m-CPBA, MCPBA, or mCPBA is metachloroperbenzoic acid; ml or mL is milliliter; min or mins is minute(s);mol is mole(s); mmol is mmole(s); mg is milligram(s); MeOH is methylalcohol or methanol; MPLC is medium pressure liquid chromatography; MSis mass spectroscopy; MsC1 or Ms-Cl is methane sulfonyl chloride; MeCNis acetonitrile; Mel is methyl iodide; MTBE is methyl tert-butyl ether;N is normal; NaHMDS is sodium hexamethyl disilazide; NH₄OAc is ammoniumacetate; NBS is N-bromo succinamide; NEt₃ is triethyl amine; NMP is1-methyl-2-pyrrolidinone; NMR is nuclear magnetic resonancespectroscopy; o.n. or ON is overnight; PE is petroleum ether; PPA ispolyphosphoric acid; i-PrOH is isopropanol; Pd(OAc)₂ is palladiumacetate; Pd(PPh₃)₄ is tetrakis(triphenylphosphine)palladium; P(Ph₃)₂Cl₂is bis(triphenylphosphine)-palladium (II) dichloride; prep ispreparative; prep. TLC or prep-TLC, or prep TCL is preparative thinlayer chromatography; psi is pounds per square inch; rac is racemic; rtor r.t. or RT is room temperature; R_(f) is retention factor; sat orsat. is saturated; SFC is supercritical fluid chromatography; TBAF istetrabutylammonium fluoride; TBSC1 is tert-butyl dimethylsilyl chloride;TEA is triethyl amine; Tf is trifluoromethane sulfonyl; 2-Me THF is2-methyltetrahydrofuran; THF is tetrahydrofuran; TFA is trifluoroaceticacid; TLC is thin-layer chromatography; p-Tos, Tos and Ts are p-toluenesulfonyl; TosCl and TsC1 are p-toluene sulfonyl chloride; pTSA, pTsOHand TsOH are p-toluenesulfonic acid; Ts₂O is tosic anhydride orp-toluenesulfonic anhydride; and Xphos Pd G2 ischloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).

Several methods for preparing the compounds of this invention areillustrated in the following Scheme and Examples. Starting materials areeither commercially available or made by known procedures in theliterature or as illustrated. The present invention further providesprocesses for the preparation of compounds of structural formula I asdefined above. In some cases the order of carrying out the foregoingreaction schemes may be varied to facilitate the reaction or to avoidunwanted reaction products. The following Schemes and Examples areprovided to illustrate the invention and are not to be construed aslimiting the invention in any manner. The scope of the invention isdefined by the appended claims.

Intermediate 11,1,1-trifluoro-N-[2-(4-oxo-3,4-dihydro-2H-1-benzopyran-7-yl)phenyl]methanesulfonamide

Step 1: 3-(3-bromophenoxy)propanenitrile

Into a 10-mL 4-necked round-bottom flask, purged and maintained with aninert atmosphere of nitrogen, was placed 3-bromophenol (800 g, 4.62 mol,1.00 equiv), and 2-methylpropan-2-ol (2 L, 1.00 eq), followed by theaddition of potassium hydroxide (18 g, 0.07 equiv) in several batches.Then prop-2-enenitrile (739 g, 13.93 mol, 3 eq) was added in severalbatches. The reaction was stirred for 4 h at 70° C. in an oil bath. Thenadded prop-2-enenitrile (355 g, 1.50 equiv), and potassium hydroxide (4g, 0.01 equiv) were added, and the reaction was stirred for 44 h whilethe temperature was maintained at 70° C. in an oil bath. The resultingmixture was concentrated under vacuum, then diluted with ethyl acetate(10 L), and washed with of 0.5M sodium hydroxide (5×4 L) and of H₂O (1×4L), and brine (1×4 L). The organic layer was separated and dried overanhydrous sodium sulfate and concentrated under vacuum. The resultingresidue was purified on a silica gel column eluted with ethylacetate/petroleum ether (1:15) to give the title compound.

Step 2: 3-(3-bromophenoxy)propanoic Acid

A solution of 3-(3-bromophenoxy)propanenitrile (310 g, 1.37 mol, 1.00equiv), and conc. HCl (750 mL) was stirred for 3 h at 90° C. Then thereaction was quenched by the addition of water (1.5 L). The resultingsolids were collected by filtration, washed with H₂O (2 L) and n-hexane(1 L), and dried in an oven to give the title compound.

Step 3: 7-bromo-3,4-dihydro-2H-1-benzopyran-4-one

Into a 3-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed 3-(3-bromophenoxy)-propanoicacid (195 g, 795.69 mmol, 1.00 equiv), and PPA (2008 g). The reactionwas stirred for 2 h at 70° C. in an oil bath, then slowly poured into 2L of ice. The resulting solids were collected by filtration, andpurified by Prep-SFC (Column, AD-H; mobile phase, methanol:MeCN=1:1;Detector, UV, 220, 254 nm) to give the title compound.

Step 4: 7-(2-aminophenyl)-3,4-dihydro-2H-1-benzopyran-4-one

Into a 2-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed 3-(3-bromophenoxy)propanoicacid (73 g, 297.87 mmol, 1.00 equiv), tetrahydrofuran (750 mL),2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (57 g, 260.17 mmol, 1.30equiv), 1M K₃PO₄ (307 mL, 3.00 equiv), and Pd(dppf)Cl₂ (25 g, 34.17mmol, 0.10 equiv). The resulting solution was stirred for 4 h at 60° C.in an oil bath, then extracted with of ethyl acetate (2×500 mL). Thecombined organic layers were washed with of water (1×500 mL) and ofbrine (1×500 mL), then dried over anhydrous sodium sulfate andconcentrated under vacuum. The resulting residue was purified on asilica gel column eluting with ethyl acetate/hexane (1:10) to give thetitle compound.

Step 5:1,1,1-trifluoro-N-[2-(4-oxo-3,4-dihydro-2H-1-benzopyran-7-yl)phenyl]methanesulfonamide

Into a 1-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed7-(2-aminophenyl)-3,4-dihydro-2H-1-benzopyran-4-one (45 g, 188.07 mmol,1.00 equiv), dichloromethane (450 mL), and TEA (28 g, 276.71 mmol, 1.50equiv). Then (trifluoromethane)sulfonyltrifluoromethanesulfonate (56 g,198.48 mmol, 1.05 equiv) was added dropwise with stirring in 20 min. Theresulting solution was stirred for 3 h at 0° C. in a liquid nitrogenbath, then quenched by the addition of water (50 mL). The resultingsolution was extracted with dichloromethane (2×500 mL) and the combinedorganic layers were washed with brine (1×500 mL), and dried overanhydrous sodium sulfate. The resulting residue was applied onto asilica gel column and eluted with ethyl acetate/PE (1:5) to give thetitle compound. MS ES calcd for C₁₆H₁₂F₃NO₄S [M+H]⁺ 472, found 472.¹H-NMR—(400 MHz, CDCl₃, ppm): δ 2.86-2.89 (2H, m), 4.59-4.63 (2H, m),6.76 (1H, s), 6.96-7.00 (2H, m), 7.26-7.28 (2H, m), 7.30-7.36 (1H, d),7.64-7.65 (1H, m), 7.99-8.01 (1H, m).

Intermediate 2 Synthesis of (3S,4R or3R,4S)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol,and (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol

Step 1: (E)-7-bromo-3-(pyridin-2-ylmethylene)chroman-4-one

7-Bromochroman-4-one (15.0 g, 66.1 mmol), picolinaldehyde (8.49 g, 79mmol), pyrrolidine (6.56 ml, 79 mmol) and MeOH (50 ml) were combined,placed under an argon atmosphere and stirred for 16 hours. The resultingsolid was filtered, washed with MeOH (30 ml) and dried under vacuum toobtain the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.72-8.71 (m, 1H),7.87 (d, J=9.6 Hz, 1H), 7.78-7.69 (m, 2H), 7.50 (d, J=8.4 Hz, 1H),7.28-7.17 (m, 3H), 5.92 (s, 2H).

Step 2: 7-bromo-3-(pyridin-2-ylmethyl)chroman-4-one

(E)-7-Bromo-3-(pyridin-2-ylmethylene)chroman-4-one (18.3 g, 57.9 mmol),diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (19.06 g, 75mmol), silica (110 g, 1.83 mol) and degassed toluene (180 mL) werecombined. The mixture was placed under nitrogen atmosphere and refluxedfor 20 hours, then filtered. The filtrate was concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica (0-50% EtOAc/hexanes) to obtain the title compound. MS ESI calcd.for C₁₅H₁₃BrNO₂ [M+H]⁺ 319, found 319.

Step 3: Mixture of (rac-cis)-7-bromo-3-(pyridin-2-ylmethyl)chroman-4-oland (rac-trans)-7-bromo-3-(pyridin-2-ylmethyl)chroman-4-ol

A mixture of 7-Bromo-3-(pyridin-2-ylmethyl)chroman-4-one (14.5 g, 45.6mmol), sodium borohydride (3.45 g, 91 mmol) and methanol (80 mL) wasplaced under a nitrogen atmosphere and stirred for 3 hours. The reactionmixture was then poured into saturated aqueous ammonium chloride (30mL), extracted with ethyl acetate (x2), dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica (0-70%EtOAc/hexanes) to obtain(rac-cis)-7-bromo-3-(pyridin-2-ylmethyl)chroman-4-ol (first eluting): MSESI calcd. for C₁₅H₁₅BrNO₂ [M+H]⁺ 321, found 321; and(rac-trans)-7-bromo-3-(pyridin-2-ylmethyl)chroman-4-ol (second eluting):MS ESI calcd. for C₁₅H₁₅BrNO₂ [M+H]⁺321, found 321.

Step 4

(rac-trans)-7-Bromo-3-(pyridin-2-ylmethyl)chroman-4-ol (1.0 g, 3.12mmol) was separated into single enantiomers using a Chiralpak ADpreparative HPLC column (95:5 to 90:10 heptane/2-propanol, 0.1%diethylamine) to give: Enantiomer A [1st eluted enantiomer]-(3S,4R or3R,4S)-7-bromo-3-(pyridin-2-ylmethyl)chroman-4-ol (MS ESI calcd. forC₁₅H₁₅BrNO₂ [M+H]⁺ 321, found 321); and Enantiomer B [2nd elutedenantiomer]-(3R,4S or 3S,4R)-7-bromo-3-(pyridin-2-ylmethyl)chroman-4-ol(MS ESI calcd. for C₁₅H₁₅BrNO₂ [M+H]⁺ 321, found 321).

Step 5: (3S,4R or3R,4S)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol

A mixture of (3S,4R or 3R,4S)-7-Bromo-3-(pyridin-2-ylmethyl)chroman-4-ol(1.5 g, 4.68 mmol), bis(pinacolato)diboron (1.31 g, 5.16 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.343 g,0.468 mmol), potassium acetate (1.15 g, 11.73 mmol) and 1,4-dioxane (30ml) was stirred at 80° C. for 16 hours. The reaction mixture wasconcentrated, diluted with water and extracted with ethyl acetate (x2).The combined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica (0-70% EtOAc-Hexanes) to obtain thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 8.53-8.52 (m, 1H), 7.65-7.62(m, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.26 (s, 1H),7.17-7.15 (m, 1H), 4.63 (d, J=6.4 Hz, 1H), 4.24 (dd, J=11.6 Hz, 3.2 Hz,1H), 3.98 (dd, J=11.2 Hz, 7.6 Hz, 1H), 2.94 (dd, J=14.0 Hz, 7.2 Hz, 1H),2.78 (dd, J=14.4 Hz, 6.4 Hz, 1H), 2.51-2.49 (m, 1H), 1.33 (s, 12H).

Step 6: (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(44,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol

The title compound was prepared according to the procedure of Example 75Step 5 starting from (3R,4S or3S,4R)-7-bromo-3-(pyridin-2-ylmethyl)chroman-4-ol (2nd elutedenantiomer). ¹H NMR (400 MHz, CDCl₃) δ 8.54-8.53 (m, 1H), 7.65-7.61 (m,1H), 7.46 (d, J=7.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.27 (s, 1H),7.18-7.15 (m, 1H), 4.62 (d, J=6.4 Hz, 1H), 4.25 (dd, J=11.2 Hz, 3.2 Hz,1H), 3.98 (dd, J=11.2 Hz, 8.0 Hz, 1H), 2.94 (dd, J=14.8 Hz, 7.2 Hz, 1H),2.78 (dd, J=14.8 Hz, 6.4 Hz, 1H), 2.51-2.49 (m, 1H), 1.33 (s, 12H).

Examples 1 and 2N-(2-((3,4-Rac-cis)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide(1) andN-(2-((3,4-Rac-trans)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide(2)

Step 1

1,1,1-Trifluoro-N-(2-(4-oxochroman-7-yl)phenyl)methanesulfonamide (350mg, 0.943 mmol), pyrrolidine (80 mg, 1.131 mmol), benzaldehyde (120 mg,1.131 mmol) and methanol (3 mL) were combined, placed under an argonatmosphere, and stirred for 3 hours. Then the reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by column chromatography on silica (0-20% EtOAc/hexanes) toafford(E)-N-(2-(3-benzylidene-4-oxochroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide.MS ESI calculated. for C₂₃H₁₇F₃NO₄S [M+H]⁺ 460, found 460.

Step 2

(E)-N-(2-(3-Benzylidene-4-oxochroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide(product of Step 1, 390 mg, 0.849 mmol), 10% palladium on carbon (90 mg,0.085 mmol) and degassed ethyl acetate (3 mL) were combined. Thereaction mixture was placed under a hydrogen atmosphere, and evacuatedand purged with hydrogen two times. Then the reaction was stirred for 30minutes under a hydrogen atmosphere (balloon). Then the reaction mixturewas diluted with ethyl acetate, filtered through Celite™, and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica (0-20% EtOAc/hexanes) toaffordN-(2-(3-benzyl-4-oxochroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide.MS ESI calcd. for C₂₃H₁₉F₃NO₄S[M+H]⁺ 462, found 462.

Step 3

A mixture ofN-(2-(3-Benzyl-4-oxochroman-7-yl)phenyl)-1,1,1-trifluoromethane-sulfonamide(product of Step 2, 360 mg, 0.780 mmol), sodium borohydride (59 mg,1.560 mmol) and ethanol (5 mL) was placed under a nitrogen atmosphereand stirred for 3 hours. Then the reaction mixture was poured intosaturated aqueous ammonium chloride (10 mL), extracted with ethylacetate (x2), dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica (0-40% EtOAc/hexanes) to affordN-(2-((cis)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide,1 (first eluting): MS ESI calcd. for C₂₃H₂₁F₃NO₄S [M+H]⁺ 464, found 464.¹H NMR (400 MHz, CD₃OD) δ 7.43-7.36 (m, 3H), 7.35-7.26 (m, 6H),7.24-7.16 (m, 1H), 6.92 (d, J=7.9, 1.7 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H),4.58 (d, J=3.2 Hz, 1H), 4.13-4.00 (m, 2H), 2.93 (dd, J=14.0, 7.3 Hz,1H), 2.62 (dd, J=13.5, 8.4 Hz, 1H), 2.34-2.24 (m, 1H); andN-(2-((trans)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluorometh-anesulfonamide,2 (second eluting): MS ESI calcd. for C₂₃H₂₁F₃NO₄S [M+H]⁺ 464, found464. ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.34 (m, 5H), 7.33-7.25 (m, 2H),7.24-7.16 (m, 3H), 6.98 (dd, J=7.7, 1.7 Hz, 1H), 6.88 (d, J=1.6 Hz, 1H),4.46 (d, J=4.3 Hz, 1H), 4.42 (dd, J=10.9, 2.5 Hz, 1H), 3.97 (dd, J=10.7,4.5 Hz, 1H), 2.77 (dd, J=13.8, 6.6 Hz, 1H), 2.54 (dd, J=13.6, 8.8 Hz,1H), 2.25-2.16 (m, 1H).

Example 3N-(2-((3,4-Rac-cis)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

This compound was synthesized according to the procedure described forExample 1 (first eluting), starting with the appropriate startingmaterials. MS ESI calcd. for C₂₉H₂₃F₃NO₄S [M−H]⁻ 538, found 538. ¹H NMR(400 MHz, CD₃OD) δ 7.64-7.54 (m, 4H), 7.45-7.27 (m, 10H), 6.93 (dd,J=7.8, 1.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 4.61 (d, J=3.3 Hz, 1H),4.16-4.00 (m, 2H), 2.97 (dd, J=13.4, 7.4 Hz, 1H), 2.68 (dd, J=13.7, 7.9Hz, 1H), 2.40-2.28 (m, 1H).

Example 4N-(2-((3,4-Rac-trans)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₉H₂₃F₃NO₄S [M−H]⁻ 538, found 538. ¹H NMR (400 MHz,CD₃OD) δ 7.64-7.52 (dd, J=7.5 Hz, 4H), 7.46-7.34 (m, 7H), 7.34-7.25 (m,3H), 6.99 (d, J=7.8 Hz, 1H), 6.89 (s, 1H), 4.50 (d, J=4.2 Hz, 1H), 4.27(dd, J=11.3, 2.6 Hz, 1H), 4.02 (dd, J=11.0, 4.1 Hz, 1H), 2.81 (dd,J=14.0, 6.6 Hz, 1H), 2.59 (dd, J=13.1, 9.1 Hz, 1H), 2.31-2.20 (m, 1H).

Example 51,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-phenylthiophen-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₇H₂₁F₃NO₄S₂[M−H]⁻ 544, found 544. ¹H NMR (400 MHz,CD₃OD) δ 7.61-7.55 (m, 2H), 7.45-7.32 (m, 8H), 7.27-7.23 (m, 1H), 7.22(d, J=3.8 Hz, 1H), 6.99 (dd, J=7.8, 1.8 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H),6.81 (d, J=3.6 Hz, 1H), 4.55 (d, J=4.4 Hz, 1H), 4.33 (dd, J=11.0, 2.6Hz, 1H), 4.11 (dd, J=11.7, 4.7 Hz, 1H), 2.97 (dd, J=15.0, 6.7 Hz, 1H),2.82 (dd, J=15.1, 8.6 Hz, 1H), 2.34-2.22 (m, 1H).

Example 6N-(2-((3,4-Rac-trans)-3-((1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₀H₁₉F₃N₃O₄S [M+H]⁺ 454, found 454. ¹H NMR (400 MHz,CD₃OD) δ 7.53 (d, J=2.0 Hz, 1H), 7.46-7.32 (m, 5H), 6.98 (dd, J=8.0, 1.8Hz, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.17 (d, J=2.0 Hz, 1H), 4.48 (d, J=4.7Hz, 1H), 4.27 (dd, J=11.1, 4.9 Hz, 1H), 4.01 (dd, J=10.9, 5.2 Hz, 1H),2.81 (dd, J=14.1, 6.1 Hz, 1H), 2.65 (dd, J=13.5, 8.5 Hz, 1H), 2.30-2.24(m, 1H).

Example 71,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(pyridin-3-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₂H₁₈F₃N₂O₄S [M−H]⁻ 463, found 463. ¹H NMR (400 MHz,CD₃OD) δ 8.41-8.39 (m, 2H), 7.75-7.72 (m, 1H), 7.42-7.35 (m, 6H), 7.00(d, J=8.0 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 4.46 (d, J=4.4 Hz, 1H), 4.26(dd, J=12.0, 4.0 Hz, 1H), 3.97 (dd, J=12.0, 4.0 Hz, 1H), 2.81 (dd,J=16.0, 8.0 Hz, 1H), 2.62 (dd, J=16.0, 8.0 Hz, 1H), 2.25-2.24 (m, 1H).

Example 81,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-3-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₁H₁₇F₃NO₄S₂[M−H]⁻ 468, found 468. ¹H NMR (400 MHz,CD₃OD) δ 7.40-7.34 (m, 6H), 7.05 (s, 1H), 7.00-6.96 (m, 2H), 6.86 (d,J=1.6 Hz, 1H), 4.46 (d, J=4.4 Hz, 1H), 4.26 (dd, J=10.8, 4.2 Hz, 1H),3.99 (dd, J=10.8, 4.0 Hz, 1H), 2.79 (dd, J=14.4, 6.4 Hz, 1H), 2.63 (dd,J=14.0, 8.0 Hz, 1H), 2.27-2.23 (m, 1H).

Example 91,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiazol-5-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₀H₁₈F₃N₂O₄S₂ [M+H]⁺471, found 471. ¹H NMR (400 MHz,CD₃OD) δ 8.90 (s, 1H), 7.64 (s, 1H), 7.40-7.36 (m, 5H), 7.01-6.99 (m,1H), 6.89 (d, J=2.0 Hz, 1H), 4.49 (d, J=4.4 Hz, 1H), 4.29 (dd, J=11.2,2.8 Hz, 1H), 4.04 (dd, J=10.4, 4.0 Hz, 1H), 3.02 (dd, J=14.0, 6.0 Hz,1H), 2.92 (dd, J=14.4, 8.0 Hz, 1H), 2.25-2.23 (m, 1H).

Example 101,1,1-Trifluoro-N-(2-((3,4-rac-cis)-4-hydroxy-3-(thiazol-5-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 1 (first eluting) using the appropriate starting materials. MSESI calcd. for C₂₀H₁₈F₃N₂O₄S₂ [M+H]⁺471, found 471. ¹H NMR (400 MHz,CD₃OD) δ 8.90 (s, 1H), 7.75 (s, 1H), 7.37-7.32 (m, 5H), 6.97-6.94 (m,1H), 6.86 (d, J=1.6 Hz, 1H), 4.63 (s, 1H), 4.11-4.08 (m, 2H), 3.18 (dd,J=14.4, 7.6 Hz, 1H), 2.98 (dd, J=14.4, 7.6 Hz, 1H), 2.34-2.31 (m, 1H).

Example 111,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-methylpyridin-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₃H₂₂F₃N₂O₄S [M+H]⁺ 479, found 479. ¹H NMR (400 MHz,CD₃OD) δ 8.32 (s, 1H), 7.62-7.58 (m, 1H), 7.39-7.34 (m, 5H), 7.18 (d,J=8.0 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.88 (d, J=1.6 Hz, 1H), 4.46 (d,J=4.4 Hz, 1H), 4.26 (dd, J=11.2, 2.8 Hz, 1H), 3.99 (dd, J=11.0, 3.2 Hz,1H), 2.85 (dd, J=14.0, 6.8 Hz, 1H), 2.72 (dd, J=14.4, 8.0 Hz, 1H),2.41-2.37 (m, 1H), 2.34 (s, 3H).

Example 12N-(2-((3,4-Rac-trans)-3-((1H-pyrazol-4-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

This compound was synthesized according to the procedure described forExample 2 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₀H₁₉F₃N₃O₄S [M+H]⁺ 454, found 454. ¹H NMR (400 MHz,CD₃OD): δ 7.45 (s, 2H), 7.40-7.33 (m, 5H), 6.98 (dd, J=11.0, 2.7 Hz,1H), 6.87 (d, J=1.7 Hz, 1H), 4.46 (d, J=4.5 Hz, 1H), 4.28 (dd, J=11.0,2.7 Hz, 1H), 4.00 (dd, J=11.0, 5.0 Hz, 1H), 2.65 (dd, J=14.7, 6.5 Hz,1H), 2.49 (dd, J=14.7, 8.5 Hz, 1H), 2.15-2.10 (m, 1H).

Example 131,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((1-methyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 1 (first eluting) using the appropriate starting material. MSESI calcd. for C₂₁H₁₉F₃N₃O₄S [M−H]⁻ 466, found 466. ¹H NMR (400 MHz,CD₃OD) δ 7.48 (d, J=2.2 Hz, 1H), 7.42-7.30 (m, 5H), 6.97 (dd, J=8.6, 1.9Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 6.20 (d, J=2.1 Hz, 1H), 4.49 (d, J=4.9Hz, 1H), 4.27 (dd, J=11.3, 2.9 Hz, 1H), 4.01 (dd, J=11.2, 5.2 Hz, 1H),2.75 (dd, J=15.1, 6.8 Hz, 1H), 2.57 (dd, J=15.1, 8.9 Hz, 1H), 2.30-2.21(m, 1H).

TABLE 1 Examples 14-23 were prepared according to the procedure ofExamples 1 and 2, starting with the appropriate starting materials. Ex-Exact Mass ample Structure Name [M + H]+ 14

1,1,1-Trifluoro-N-(2-{(rac-trans)- 4-hydroxy-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-3,4-dihydro- 2H-chromen-7-yl}phenyl)methanesulfonamide Calc'd [M − H]⁻ 529, found 529

15

1,1,1-Trifluoro-N-{2-[(rac-trans)- 4-hydroxy-3-(1,3-oxazol-2-ylmethyl)-3,4-dihydro-2H- chromen-7- yl]phenyl}methanesulfonamide Calc'd[M − H]⁻ 453, found 453

16

1,1,1-Trifluoro-N-(2-{(rac- trans)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4- dihydro-2H- chromen-7-yl}phenyl)methanesulfonamide Calc'd [M − H]⁻ 483, found 483

17

N-(2-{(rac-trans)-3-[(2- cyclopropyl-1,3-thiazol-4-yl)methyl]-4-hydroxy- 3,4-dihydro-2H-chromen-7- yl}phenyl)-1,1,1-trifluoromethanesulfonamide Calc'd [M + H]⁺ 511, found 511

18

1,1,1-Trifluoro-N-(2-{(rac-trans)- 4-hydroxy-3-[(1-methyl-1H-pyrazol-3-yl)methyl]-3,4- dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide Calc'd [M + H]⁺ 468, found 468

19

1,1,1-Trifluoro-N-(2-{(rac-trans)- 3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4-dihydro-2H- chromen-7-yl}phenyl) methanesulfonamide Calc'd[M − H]⁻ 481, found 481

20

1,1,1-Trifluoro-N-(2-{(rac-trans)- 4-hydroxy-3-[(6-methylpyridin-2-yl)methyl]-3,4-dihydro-2H- chromen-7-yl}phenyl) methanesulfonamideCalc'd [M − H]⁻ 477, found 477

21

1,1,1-Trifluoro-N-(2-{(rac-trans)- 4-hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H- chromen-7-yl}phenyl) methanesulfonamideCalc'd [M − H]− 477, found 477

22

1,1,1-Trifluoro-N-(2-{(rac-trans)- 4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4- dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide Calc'd [M + H]⁺ 485, found 485

23

1,1,1-Trifluoro-N-(2-{(rac-trans)- 4-hydroxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-3,4- dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide Calc'd [M − H]− 484, found 484

24

1,1,1-Trifluoro-N-(2-((rac-trans)- 4-hydroxy-3-((2-phenylthiazol-4-yl)methyl)chroman-7- yl)phenyl)methanesulfonamide Calc'd [M − H]⁻ 545,found 545

Examples 25 and 26 1,1,1-trifluoro-N-{2-[(3R,4S or3S,4R)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide(25) and 1,1,1-trifluoro-N-{2-[(3 S,4R or3R,4S)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide(26)

Step 1

1,1,1-Trifluoro-N-(2-(4-oxochroman-7-yl)phenyl)methanesulfonamide (330mg, 0.89 mmol), isonicotinaldehyde (150 mg, 1.4 mmol), piperidine (1.5mL) and acetic acid (1.5 mL) were combined in a sealed tube. The mixturewas heated to 130° C. for 4 h. Then the solvent was removed underreduced pressure. The resulting crude material was dissolved in water(10 mL) and neutralized with saturated aqueous NaHCO₃. The mixture wasextracted with ethyl acetate (10 mL×3), dried over Na₂SO₄ andconcentrated. The resulting crude product was purified by chromatographyon silica (0-10% MeOH/CH₂Cl₂) to afford(E)-1,1,1-trifluoro-N-(2-(4-oxo-3-(pyridin-4-ylmethylene)chroman-7-yl)phenyl)methane-sulfonamide.MS ESI calcd. for C₂₂H₁₆F₃N₂O₄S [M+H]⁺ 461, found 461.

Step 2

To a solution of(E)-1,1,1-trifluoro-N-(2-(4-oxo-3-(pyridin-4-ylmethylene)chroman-7-yl)phenyl)methanesulfonamide(product of Step 1, 100 mg, 0.217 mmol) in methanol (6 ml) was addedsodium borohydride (25 mg, 0.65 mmol). The reaction was stirred at roomtemperature for 16 h, then the methanol was evaporated under reducedpressure and water (10 mL) was added. The reaction mixture was acidifiedto pH˜5-6 with 2N HCl, extracted with ethyl acetate (3×), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting crude product was purified by chromatography on silica (0-10%MeOH/CH₂Cl₂) to afford1,1,1-trifluoro-N-(2-(4-hydroxy-3-(pyridin-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamideas a 1:1 mixture of cis- and trans-isomers. MS ESI calcd. forC₂₂H₂₀F₃N₂O₄S [M+H]⁺ 465, found 465. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (s,1H), 8.16 (d, J=8 Hz, 1H), 7.68 (s, 1H), 7.55-7.53 (m, 1H), 7.44-7.38(m, 3H), 7.37-7.33 (m, 2H), 7.00-6.86 (m, 2H), 4.56-4.46 (m, 1H),4.28-3.96 (m, 2H), 3.01-2.60 (m, 2H), 2.40-2.29 (m, 1H).

Step 3

The racemic mixture of Step 2 was purified by chiral SFC (IA column,20%/80% methanol+0.25% dimethyl ethyl amine/CO₂) to afford1,1,1-trifluoro-N-(2-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide(Isomer 1, first eluting): MS ESI calcd. for C₂₂H₂₀F₃N₂O₄S [M+H]⁺ 465,found 465 and 1,1,1-trifluoro-N-(2-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide(Isomer 2, second eluting): MS ESI calcd. for C₂₂H₂₀F₃N₂O₄S [M+H]⁺ 465,found 465.

TABLE 2 Examples 27-29 were prepared according to the procedure ofExamples 25 and 26, starting with the appropriate starting materials.Exact Mass Example Structure Name [M + H]+ 27

1,1,1-Trifluoro-N-{2-[(rac-trans)-4- hydroxy-3-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-chromen-7- yl]phenyl}methanesulfonamide Calc'd [M − H]⁻ 464,found 464

28

1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(pyridazin-3-ylmethyl)-3,4- dihydro-2H-chromen-7-yl]phenyl}methane-sulfonamide Calc'd [M − H]⁻ 464, found 464

29

1,1,1-Trifluoro-N-(2-((rac-trans)-3- ((5-fluoropyridin-2-yl)methyl)-4-hydroxychroman-7- yl)phenyl)methanesulfonamide Calc'd [M − H]⁻ 481,found 481

Example 30N-(2-((3,4-Rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

Step 1

Degassed THF (30 ml) and water (6 ml) were added to a 250 ml flaskcontaining 7-bromochroman-4-one (5 g, 22 mmol), 2-(aminophenyl)boronicacid (3.02 g, 22 mmol), K₃PO₄ (9.35 g, 44 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(866 mg, 1.1 mmol). The mixture was placed under an argon atmosphere,and evacuated and purged with nitrogen three times. The reaction washeated at 60° C. for 16 h, then cooled to room temperature and thesolvent was evaporated under reduced pressure. The resulting crudeproduct was diluted with water (50 ml), extracted with ethyl acetate(x2), dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography on silica (0-60% EtOAc/hexanes) to afford7-(2-aminophenyl)chroman-4-one: MS ESI calcd. for C₁₅H₁₄NO₂ [M+H]⁺240,found 240.

Step 2

To a solution of triethylamine (0.78 ml, 5.64 mmol) in anhydrousdichloromethane (20 ml) at 0° C., were added methanesulfonyl chloride(255 mg, 1.88 mmol) followed by 7-(2-aminophenyl)chroman-4-one (productof Step 1, 455 mg, 1.88 mmol). The reaction mixture allowed to warm toroom temperature and stirred for 2 h. The reaction mixture was dilutedwith water (50 ml), acidified to pH ˜4 with 1N HCl, extracted withdichloromethane (3×), dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica (0-60% EtOAc/hexanes) toafford N-(2-(4-oxochroman-7-yl)phenyl)methanesulfonamide. MS ESI calcd.for C₁₆H₁₆NO₄S [M+H]⁺318, found 318.

Step 3

To a stirred solution ofN-(2-(4-oxochroman-7-yl)phenyl)methanesulfonamide (product of Step 2,350 mg. 11 mmol) in MeOH (5 mL) was added picolinaldehyde (154 mg, 1.4mmol), followed by pyrrolidine (0.13 mL, 1.6 mmol). The mixture wasstirred at room temperature for 16 h, then evaporated under reducedpressure. The resulting crude residue was purified by columnchromatography on silica (0-11% MeOH/CH₂Cl₂). MS ESI calcd. forC₂₂H₁₉N₂O₄S [M+H]⁺ 407, found 407.

Step 4

To a solution of(E)-N-(2-(4-oxo-3-(pyridin-2-ylmethylene)chroman-7-yl)phenyl)me-thanesulfonamide(product of Step 3, 200 mg, 0.49 mmol) in degassed EtOAc (50 ml), wasadded 10% palladium on carbon (50 mg, 0.047 mmol). The reaction wasplaced under a hydrogen atmosphere, and evacuated and purged withhydrogen two times. The reaction was stirred for 3 h under hydrogenatmosphere. The reaction mixture was diluted with ethyl acetate,filtered through Celite™, and the filtrate was concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica (0-20% EtOAc/hexanes) to affordN-(2-(4-oxo-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide.MS ESI calcd. for C₂₂H₂₁N₂O₄S [M+H]⁺ 409, found 409.

Step 5

To a stirred solution ofN-(2-(4-oxo-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methane-sulfonamide(product of Step 4, 190 mg, 0.65 mmol) in EtOH (20 mL), was added NaBH₄(52 mg, 1.3 mmol) at room temperature and stirred for 2 h. Then the EtOHwas evaporated under reduced pressure. The resulting residue was dilutedwith water (15 mL), extracted with CH₂Cl₂ (x3), dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography on silica (0-40%EtOAc/hexanes) to affordN-(2-((cis)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide)(first eluting): MS ESI calcd. for C₂₂H₂₃N₂O₄S [M+H]⁺411, found 411; and(N-(2-((trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide)30 (second eluting): MS ESI calcd. for C₂₂H₂₃N20₄S [M+H]411, found 411.¹H NMR (400 MHz, CD₃OD) δ 8.48 (d, J=5.0 Hz, 1H), 7.78 (d, J=8.5 Hz,1H), 7.50 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.50-7.41 (m, 5H),4.49 (d, J=5.0 Hz, 1H), 4.27 (dd, J=11.3, 3.0 Hz, 1H), 3.90 (dd, J=11.4,4.9 Hz, 1H), 2.96 (dd, J=14.0, 6.7 Hz, 1H), 2.79-2.71 (m, 4H), 2.47-2.38(m, 1H)

Examples 31 and 321,1,1-trifluoro-N-(2-(3,4-rac-cis)-4-hydroxy-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)metha-nesulfonamide(31), and1,1,1-trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide(32)

Step 1

To a stirred solution of1,1,1-trifluoro-N-(2-(4-oxochroman-7-yl)phenyl)methanes-ulfonamide (350mg, 0.94 mmol) in MeOH (5 mL) was added thiazole-4-carbaldehdehyde (160mg, 1.41 mmol), followed by pyrrolidine (0.11 mL, 1.41 mmol). Thereaction was stirred at room temperature for 16 h. Then the methanol wasevaporated under reduced pressure and the resulting crude residue waspurified by column chromatography on silica (0-11% MeOH/CH₂C₁₋₂). MS ESIcalcd. for C₂₀H₁₄F₃N₂O₄S₂ [M+H]⁺ 467, found 467.

Step 2

(E)-1,1,1-Trifluoro-N-(2-(4-oxo-3-(thiazol-4-ylmethylene)chroman-7-yl)phenyl)meth-anesulfonamide(product of Step 1, 390 mg, 0.83 mmol), diethyl1,4-dihydro-2,6-dimethyl,-3,5-pyridinedicarboxylate (318 mg, 1.25 mmol),silica (0.2 g, 0.1 mmol) and anhydrous toluene (30 ml) were combined andheated at 70° C. for 16 h. Then the toluene was evaporated under reducedpressure and the resulting crude residue was purified by columnchromatography on silica (0-60% EtOAc/hexane) to afford1,1,1-trifluoro-N-(2-(4-oxo-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide.MS ESI calcd. for C₂₀H₁₆F₃N₂O₄S₂ [M+H]⁺ 469, found 469.

Step 3

To a stirred solution of1,1,1-trifluoro-N-(2-(4-oxo-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide(product of Step 2, 300 mg, 0.64 mmol) in EtOH (50 mL) at roomtemperature, was added NaBH₄ (72 mg, 1.92 mmol). The reaction wasstirred for 2 hours.

Then the EtOH was evaporated under reduced pressure. The resultingresidue was diluted with water (15 mL), extracted with CH₂Cl₂ (x3),dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica (0-40% EtOAc/hexanes) to afford1,1,1-trifluoro-N-(2-(cis)-4-hydroxy-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)metha-nesulfonamide(first eluting) 31: MS ESI calcd. for C₂₀H₁₆F₃N₂O₄S₂ [M−H]⁻ 469, found469. ¹H NMR (400 MHz, CD₃OD) δ 8.98 (d, J=2.0 Hz, 1H), 7.43-7.30 (m,6H), 6.93 (d, J=1.6 Hz, 1H), 6.84 (d, J=1.6 Hz, 1H), 4.58 (d, J=3.7 Hz,1H), 4.11-4.06 (m, 2H), 3.11 (dd, J=13.6, 7.0 Hz, 1H), 2.88 (dd, J=14.2,8.2 Hz, 1H), 2.56-2.46 (m, 1H); and1,1,1-trifluoro-N-(2-((trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide(second eluting) 32 (MS ESI calcd. for C₂₀H₁₆F₃N₂O₄S₂ [M−H]⁻ 469, found469). ¹H NMR (400 MHz, CD₃OD) δ 8.97 (d, J=1.9 Hz, 1H), 7.33-7.43 (m,1H), 7.25 (d, J=2.0 Hz, 1H), 6.98 (dd, J=7.8, 1.7 Hz, 1H), 6.83 (d,J=1.8 Hz, 1H), 4.48 (d, J=4.4 Hz, 1H), 4.29 (dd, J=11.0, 2.7 Hz, 1H),4.00 (dd, J=11.2, 4.9 Hz, 1H), 2.95 (dd, J=14.4, 6.6 Hz, 1H), 2.81 (dd,J=14.5, 8.5 Hz, 1H), 2.47-2.38 (m, 1H).

Example 331,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was synthesized according to the procedure described forExample 18 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₁H₁₇F₃NO₄S₂[M−H]⁻ 468, found 468. ¹H NMR (400 MHz,CD₃OD) δ 7.74-7.34 (m, 5H), 7.23 (dd, J=5.0, 1.1 Hz, 1H), 6.99-6.92 (m,2H), 6.87 (d, J=1.7 Hz, 1H), 6.83 (d, J=3.6 Hz, 1H), 4.58 (d, J=4.9 Hz,1H), 4.29 (dd, J=11.4, 2.9 Hz, 1H), 2.82 (dd, J=15.1, 8.9 Hz, 1H),2.27-2.18 (m, 1H).

Example 34N-(2-((3,4-rac-trans)-3-(benzo[b]thiophen-2-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

This compound was synthesized according to the procedure described forExample 18 (second eluting) using the appropriate starting materials. MSESI calcd. for C₂₅H₁₉F₃NO₄S₂[M−H]⁻ 518, found 518. ¹H NMR (400 MHz,CD₃OD) δ 7.78 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.40-7.36 (m,5H), 7.33-7.26 (m, 2H), 7.08 (s, 1H), 6.99 (dd, J=7.5, 1.7 Hz, 1H), 6.89(dd, J=6.8 Hz, 1.7, 1H), 4.56 (d, J=4.5 Hz, 1H), 4.34 (dd, J=11.1, 2.9Hz, 1H), 4.11 (dd, J=11.0, 4.4 Hz, 1H), 3.05 (dd, J=15.4, 6.8 Hz, 1H),2.91 (dd, J=15.0, 8.7 Hz, 1H), 2.40-2.31 (m, 1H).

Examples 35, 36 and 371,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide(35) 1,1,1-Trifluoro-N-(2-((3S,4R or3R,4S)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide(36) and 1,1,1-Trifluoro-N-(2-((3R,4S or3S,4R)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide(37)

1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)-chroman-7-yl)phenyl)methanesulfonamide34 was prepared according to the procedure of Example 1 using theappropriate starting materials. MS ESI calcd. for C₂₇H₂₅F₃N₃O₄S[M+H]⁺544, found 544. ¹H NMR (400 MHz, CD₃OD) δ 7.75-7.73 (m, 2H),7.39-7.28 (m, 8H), 7.03 (dd, J=8.0, 2.0 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H),6.51 (s, 1H), 4.50 (d, J=3.6 Hz, 1H), 4.35 (dd, J=11.2, 2.4 Hz, 1H),4.08 (dd, J=10.8, 4.0 Hz, 1H), 2.82 (dd, J=15.2, 6.8 Hz, 1H), 2.69 (dd,J=15.2, 8.8 Hz, 1H), 2.36-2.33 (m, 1H).

Chiral separation:1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide(25 mg, 0.045 mmol) was separated into single enantiomers via SFC usingAD-H column (20% MeOH, modified with 0.2% diethylamine) to giveEnantiomer A [1st eluted enantiomer], 1,1,1-trifluoro-N-(2-((3S,4R or3R,4S)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide35 (MS ESI calcd. for C₂₇H₂₅F₃N₃O₄S [M+H]⁺ 544, found 544); andEnantiomer B [2nd eluted enantiomer], 1,1,1-trifluoro-N-(2-((3R,4S or3S,4R)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide36 (MS ESI calcd. for C₂₇H₂₅F₃N₃O₄S [M+H]⁺ 544, found 544).

TABLE 3 Examples 38-49 were prepared according to the procedure ofExamples 34, 35 and 36, starting with the appropriate startingmaterials. Ex- Exact Mass ample Structure Name [M + H]+ 38

1,1,1-Trifluoro-N-(2-((rac-trans)- 4-hydroxy-3-((5-phenylpyridin-2-yl)methyl)chroman-7- yl)phenyl)methanesulfonamide Calc'd [M − H]⁻ 539,found 539

39

(2-((3S,4R or 3R,4S)-4-hydroxy- 3-((5-phenylpyridin-2-yl)methyl)chroman-7- yl)phenyl)((trifluoromethyl) sulfonyl)amide Calc'd[M − H]⁻ 539, found 539 40

(2-((3R,4S or 3S,4R)-4-hydroxy- 3-((5-phenylpyridin-2-yl)methyl)chroman-7- yl)phenyl)((trifluoromethyl) sulfonyl)amide Calc'd[M − H]⁻ 539, found 539 41

1,1,1-Trifluoro-N-(2-((rac-trans)- 4-hydroxy-3-((2-phenylthiazol-5-yl)methyl)chroman-7- yl)phenyl)methanesulfonamide Calc'd [M + H]⁺ 547,found 547

42

1,1,1-Trifluoro-N-(2- ((3S,4R or 3R,4S)-4-hydroxy-3-((2-phenylthiazol-5- yl)methyl)chroman-7-yl)phenyl)methanesulfonamide Calc'd [M + H]⁺ 547, found 547 43

1,1,1-Trifluoro-N-(2- ((3R,4S or 3S,4R)-4-hydroxy-3-((2-phenylthiazol-5-yl)methyl) chroman-7- yl)phenyl)methanesulfonamideCalc'd [M + H]⁺ 547, found 547 44

1,1,1-Trifluoro-N-(2-((3,4-trans)- 3-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methyl)-4- hydroxychroman-7-yl)phenyl) methanesulfonamideCalc'd [M − H]⁻ 548, found 548 45

N-(2-((3,4-trans)-3-((2-(tert- butyl)thiazol-4-yl)methyl)-4-hydroxychroman-7-yl)phenyl)- 1,1,1- trifluoromethanesulfonamide Calc'd[M − H]⁻ 527, found 527 46

N-(2-((3S,4R or 3R,4S)-3-((1- ethyl-1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)- 1,1,1- trifluoromethanesulfonamide Calc'd[M + H]⁺ 482, found 482 47

N-(2((3R,4S or 3S,4R)-3-((1- ethyl-1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7- yl)phenyl)-1,1,1- trifluoromethanesulfonamide Calc'd[M + H]⁺ 482, found 482 48

1,1,1-Trifluoro-N-(2-((rac- trans)-4-hydroxy-3-((1- phenyl-1H-pyrazol-5-yl)methyl)chroman-7- yl)phenyl) methanesulfonamide Calc'd [M + H]⁺ 530,found 530

49

(2-((3,4-trans)-4-hydroxy- 3-((1-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl) ((trifluoromethyl)sulfonyl)amide Calc'd[M + H]⁺ 530, found 530

TABLE 4 The following enantiomers were prepared as described in Example31 and obtained by chiral SFC separation using EC column with 25% MeOH,modified with 0.2% dimethylethylamine and 75% CO₂ as eluent. Exact MassExample Structure Name [M + Na]+ 50

1,1,1-trifluoro-N-{2-[(3R,4S or 3S,4R)-4-hydroxy-3-(1,3-thiazol-4-ylmethyl)-3,4- dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide Calc'd 493, found 493 51

1,1,1-trifluoro-N-{2-[(3S,4Ror 3R,4S)-4-hydroxy-3-(1,3-thiazol-4-ylmethyl)-3,4- dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide Calc'd 493, found 493

TABLE 5 The following enantiomers were prepared as described in Example22 and obtained by chiral SFC separation using IF column with MeOH,modified with 0.2% dimethylethylamine and CO₂ as eluents. Exact MassExample Structure Name [M + H]+ 52

1,1,1-trifluoro-N-(2-{(3S,4R or 3R, 4S)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide Calc'd 485, found 485 53

1,1,1-trifluoro-N-(2-{(3R,4S or 3S, 4R)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide Calc'd 485, found 485

TABLE 6 The following enantiomers were prepared similar to protocoldescribed for Example 2 and obtained by chiral SFC separation using OD-Hcolumn with MeOH, modified with 0.25% dimethylethylamine and CO₂ aseluents. Exact Mass Example Structure Name [M + H]+ 54

1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide Calc'd 465, found 465 55

1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide Calc'd 465, found 465 56

1,1,1-Trifluoro-N-(2-{(3R,4S or 3S,4R)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4- yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)-methanesulfonamide Calc'd [M − H]⁻ 483, found 483 57

1,1,1-Trifluoro-N-(2-{(3S,4R or 3R,4S)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4- yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)-methanesulfonamide Calc'd [M − H]⁻ 483, found 483 58

N-{2-[(3R,4S or 3S,4R)-3-benzyl-4- hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1- trifluoromethanesulfonamide Calc'd [M + Na]+ 486,found 486 59

N-{2-[(3S,4R or 3R,4S)-3-benzyl-4- hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1- trifluoromethanesulfonamide Calc'd [M + Na]+ 486,found 486 60

1,1,1-Trifluoro-N-(2-{(3,4-trans)-4- hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen- 7-yl}phenyl)methanesulfonamide Calc'd[M − H]− 477, found 477

TABLE 7 The following enantiomers were prepared as in Example 32 andobtained by chiral SFC separation using IC column with MeOH, modifiedwith 0.25% dimethylethylamine and CO₂ as eluents. Exact Mass ExampleStructure Name [M + H]+ 61

1,1,1-trifluoro-N-{2-[(3R,4S or 3S,4R)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4- dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide Calc'd [M + Na]+ 492, found 492 62

1,1,1-trifluoro-N-{2-[(3S,4R or 3R,4S)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4- dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide Calc'd [M + Na]+ 492, found 492

TABLE 8 The following enantiomers were prepared as in Example 20 andobtained by chiral SFC separation using of the racemate using OJ-Hcolumn with MeOH, modified with 0.25% dimethylethylamine/ CO₂ aseluents. Exact Mass Example Structure Name [M + H]+ 63

1,1,1-Trifluoro-N-(2-{(3,4-trans)-4- hydroxy-3-[(6-methyl-pyridin-2-yl)methyl]-3,4-dihydro-2H-chromen- 7-yl}-phenyl)methanesulfonamideCalc'd [M − H]− 477, found 477

TABLE 9 The following enantiomers were prepared similar to protocolsdescribed for Example 1, andobtained by chiral SFC separation of theracemate using ID column with MeOH, modified with 0.25%dimethylethylamine/CO₂ as eluents. Exact Mass Example Structure Name[M + H]+ 64

1,1,1-Trifluoro-N-(2- ((3R,4S or 3S,4R)-4- hydroxy-3-((2-phenylthiazol-4-yl)- methyl)chroman-7-yl)- phenyl)methanesulfonamideCalc'd [M − H]⁻ 545, found 545 65

1,1,1-Trifluoro-N-(2- ((3S,4R or 3R,4S)-4- hydroxy-3-((2-phenylthiazol-4-yl)- methyl)chroman-7-yl)- phenyl)methanesulfonamideCalc'd [M − H]⁻ 545, found 545 66

1,1,1-trifluoro-N-(2-{(3,4- trans)-4-hydroxy-3-[(1- methyl-1H-pyrazol-5-yl)methyl]-3,4-di-hydro-2H- chromen-7-yl}- phenyl)methanesulfonamideCalc'd 468, found 468

TABLE 10 The following enantiomers were prepared similar to protocolsdescribed for Example 1, followed by chiral SFC separation of theracemate using AD-H column MeOH, modified with 0.25% dimethylethylamine/CO₂ as eluents. Exact Mass Example Structure Name [M + H]+ 67

N-{2-[(3S,4R or 3R,4S)-3- (biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H- chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide Calc'd [M + Na]+562, found 562 68

N-{2-[(3R,4S or 3S,4R)-3- (biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H- chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide Calc'd [M + Na]+562, found 562 69

1,1,1-Trifluoro-N-(2-{(3,4- trans)-3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4- dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide Calc'd [M − H]⁻ 481, found 481 70

1,1,1-Trifluoro-N-(2-{(3,4- trans)-4-hydroxy-3-[(5-methyl-1,3,4-thiadiazol-2- yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)- methanesulfonamide Calc'd [M − H]− 484, found 484

TABLE 11 The following enantiomers were prepared as described in Example6, followed by chiral SFC separation of the racemate using Chromega CCCcolumn with MeOH, modified with 0.25% dimethylethylamine/ CO₂ aseluents. Exact Mass Example Structure Name [M + H]+ 71

1,1,1-trifluoro-N-{2-[(3,4-trans)-4- hydroxy-3-(1H-pyrazol-3-ylmethyl)-3,4-dihydro-2H-chromen-7- yl]phenyl}-methanesulfonamide Calc'd 454,found 454

TABLE 12 The following enantiomers were prepared as described in Example30, followed by chiral SFC separation of the racemate using Chromega CCCcolumn with MeOH, modified with 0.25% dimethylethylamine/ CO₂ aseluents. Exact Mass Example Structure Name [M + H]+ 72

N-{2-[(3S,4R or 3R,4S)-4-hydroxy-3- (pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide Calc'd 411, found 411 73

N-{2-[(3R,4S or 3S,4R)-4-hydroxy-3- (pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide Calc'd 411, found 411

Example 741,1,1-Trifluoro-N-(3-((3,4-rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyrazin-2-yl)methanesulfonamide

Step 1: N-(3-chloropyrazin-2-yl)-1,1-trifluoromethanesulfonamide

2,3-Dichloropyrazine (300 mg, 2.014 mmol), trifluoromethanesulfonamide(300 mg, 2.014 mmol), cesium carbonate (1.247 mg, 3.83 mmol) and NMP (5mL) were combined under an argon atmosphere and heated to 130° C. for 16h. Then the reaction mixture was cooled to room temperature, washed withwater and extracted with EtOAc (10 mL×2). The organic layer wasseparated, dried over Na₂SO₄ and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silica(0-10% DCM/MeOH) to obtain the title compound. MS ESI calcd. forC₅H₂ClF₃N₃O₂S [M−H]⁻ 260, found 260.

Step 2: 1.1.1-trifluoro-N-(3-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyrazin-2-yl)methanesulfonamide

To a mixture of (3R,4S or3S,4R)-3-(Pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2 Enantiomer B, 42.1 mg, 0.115 mmol),N-(3-chloropyrazin-2-yl)-1,1,1-trifluoromethanesulfonamide (30 mg, 0.115mmol), K₃PO₄ (74 mg, 0.344 mmol), water (0.25 mL) and THF (2.5 mL),under an argon atmosphere, was added Xphos Pd G2 (9.0 mg, 0.011 mmol).The reaction was stirred at 60° C. for 16 h, then concentrated, dilutedwith water, acidified to pH˜5 and extracted with EtOAc (10 mL×2). Thecombined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica (0-10% DCM/MeOH) toobtain the title compound. MS ESI calcd. for C₂₀H₁₆F₃N₄04S [M−H]⁻ 465,found 465. ¹H NMR (400 MHz, CD₃OD) δ 8.67 (d, J=4.8 Hz, 1H), 8.38-8.37(m, 1H), 8.26 (d, J=3.6 Hz, 1H), 7.91-7.87 (m, 2H), 7.81-7.78 (m, 1H),7.56 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.47-7.42 (m, 2H), 4.56 (d, J=4.8 Hz,1H), 4.34 (dd, J=11.2 Hz, 2.8 Hz, 1H), 4.07 (dd, J=11.2 Hz, 4.8 Hz, 1H),3.13 (dd, J=13.6 Hz, 6.8 Hz, 1H), 3.06 (dd, J=11.2 Hz, 8.0 Hz, 1H),2.53-2.51 (m, 1H).

Example 75N-(2-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)-1-methylcyclopropane-1-sulfonamide

Step 1: N-(2-bromophenyl)-1-methylcyclopropane-1-sulfonamide

A mixture of 2-Bromoaniline (100 mg, 0.581 mmol),1-methylcyclopropane-1-sulfonyl chloride (270 mg, 1.744 mmol) andpyridine (0.7 mL), under argon atmosphere, was heated to 60° C. for 6 h.Then the reaction mixture was cooled to room temperature, washed with 2NHCl and extracted with EtOAc (10 mL×2). The combined organic layers wereseparated, dried over Na₂SO₄ and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silica(0-20% EtOAc/hexanes) to obtain the title compound. MS ESI calcd. forC₁₀H₁₁BrNO₂S [M−H]⁻ 288, found 288.

Step 2: N-(2-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)-1-methylcyclopropane-1-sulfonamide

To a mixture of (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2 Enantiomer B, 30 mg, 0.082 mmol),N-(2-bromophenyl)-1-methylcyclopropane-1-sulfonamide (23.7 mg, 0.082mmol), K₃PO₄ (52 mg, 0.245 mmol), water (0.2 mL) and THF (2.0 mL), underan argon atmosphere, was added Xphos Pd G2 (6.5 mg, 8.17 tmol). Thereaction stirred at 60° C. for 12 h, then concentrated, diluted withwater, acidified to pH˜5 and extracted with EtOAc (10 mL×2). Thecombined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica (0-10% DCM/MeOH) toobtain the title compound. MS ESI calcd. for C₂₅H₂₇N₂O₄S [M+H]⁺ 451,found 451. ¹H NMR (400 MHz, CD₃OD) δ 8.67 (dd, J=5.6 Hz, 0.8 Hz, 1H),8.33-8.31 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.54 (dd,J=7.6 Hz, 1.2 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.35-7.28 (m, 3H), 7.05(dd, J=8.0 Hz, 2.0 Hz, 1H), 6.92 (d, J=1.6 Hz, 1H), 4.56 (d, J=4.8 Hz,1H), 4.33 (dd, J=11.6 Hz, 2.8 Hz, 1H), 4.03 (dd, J=10.8 Hz, 5.2 Hz, 1H),3.10 (dd, J=14.4 Hz, 7.6 Hz, 1H), 3.06 (dd, J=14.4 Hz, 8.0 Hz, 1H),2.51-2.48 (m, 1H), 1.25 (s, 3H), 1.09-1.07 (m, 2H), 0.68-0.66 (m, 2H).

Example 762,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyrazin-2-yl)ethanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromopyrazin-2-yl)-2,2,2-trifluoroethanesulfonamide. MS ESI calcd.for C₂₁H₂₀F₃N₄04S [M+H]⁺ 481, found 481.

Example 77 2,2,2-Trifluoro-N-(3-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)ethanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromopyridin-2-yl)-2,2,2-trifluoroethanesulfonamide. MS ESI calcd.for C₂₂H₂₁F₃N₃O₄S [M+H]⁺ 480, found 480.

Example 78 2,2,2-Trifluoro-N-(3-((3S,4R or3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)ethanesulfonamide

This compound was prepared according to the procedure of Example 75using (3S,4R or3R,4S)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromopyridin-2-yl)-2,2,2-trifluoroethanesulfonamide. MS ESI calcd.for C₂₂H₂₁F₃N₃O₄S [M+H]⁺ 480, found 480.

Example 79 2,2,2-Trifluoro-N-(2-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)ethanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) and N-(2-bromophenyl)-2,2,2-trifluoroethanesulfonamide.MS ESI calcd. for C₂₃H₂₂F₃N₂O₄S [M+H]⁺ 479, found 479.

Example 80 2,2,2-Trifluoro-N-(2-((3S,4R or3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)ethanesulfonamide

This compound was prepared according to the procedure of Example 75using (3S,4R or3R,4S)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) and N-(2-bromophenyl)-2,2,2-trifluoroethanesulfonamide.MS ESI calcd. for C₂₃H₂₀F₃N₂O₄S [M−H]⁻ 477, found 477.

Example 81 1,1-Difluoro-N-(2-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) and N-(2-bromophenyl)-1,1-difluoromethanesulfonamide.MS ESI calcd. for C₂₂H₁₉F₂N₂O₄S [M−H]⁻ 445, found 445.

Example 82 1,1-Difluoro-N-(2-((3S,4R or3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was prepared according to the procedure of Example 75using (3S,4R or3R,4S)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) and N-(2-bromophenyl)-1,1-difluoromethanesulfonamide.MS ESI calcd. for C₂₂H₁₉F₂N₂O₄S [M−H]⁻ 445, found 445.

Example 831,1,1-Trifluoro-N-(4-fluoro-2-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(2-bromo-4-fluorophenyl)-1,1,1-trifluoromethanesulfonamide. MS ESIcalcd. for C₂₂H₁₇F₄N₂O₄S [M−H]⁻ 481, found 481.

Example 841,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromo-5-fluoropyridin-2-yl)-1,1,1-trifluoromethanesulfonamide. MSESI calcd. for C₂₁H₁₆F₄N₃O₄S [M−H]⁻ 482, found 482.

Example 851,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromo-5-fluoropyridin-2-yl)-2,2,2-trifluoroethanesulfonamide. MSESI calcd. for C₂₂H₂₀F₄N₃O₄S [M+H]⁺ 498, found 498.

Example 861,1-Difluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromopyridin-2-yl)-1,1-difluoromethanesulfonamide. MS ESI calcd.for C₂₁H₂₀F₂N₃O₄S [M+H]⁺ 448, found 448.

Example 871,1,1-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromopyridin-2-yl)-1,1,1-trifluoromethanesulfonamide. MS ESI calcd.for C₂₁H₁₉F₃N₃O₄S [M+H]±466, found 466.

Example 882,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)-5-(trifluoromethyl)pyrazin-2-yl)ethanesulfonamide

This compound was prepared according to the procedure of Example 75using (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2) andN-(3-bromo-5-(trifluoromethyl)pyrazin-2-yl)-2,2,2-trifluoroethanesulfonamide.MS ESI calcd. for C₂₂H₁₉F₆N₄04S [M+H]⁺ 549, found 549.

Examples 89 and 90 N-(6-chloro-4-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide(89) andN-(4-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoro-methanesulfonamide(90)

Step 1: N-(6-chloro-4-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1.1.1-trifluoromethanesulfonamide89

To a mixture of (3R,4S or3S,4R)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2, 30.0 mg, 0.088 mmol),N-(4-bromo-6-chloropyridazin-3-yl)-1,1-trifluoromethanesulfonamide (38.8mg, 0.106 mmol), 2M Na₂CO₃ (0.132 mL, 0.264 mmol) and 1,4-dioxane (2mL), under an argon atmosphere, was added [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (6.45 mg, 8.81 mmol). The reaction wasstirred at 100° C. for 1 h. Then the reaction mixture was diluted withEtOAc and washed with water. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by reverse phase (C₁₈) columnchromatography (20-25% acetonitrile/water) to obtain the title compound.MS ESI calcd. for C₂₀H₁₇ClF₃N₄O₄S [M+H]⁺ 501, found 501.

Step 2: 1.1.1-trifluoro-N-(4-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)methanesulfonamide90

To a mixture of N-(6-chloro-4-((3R,4S or3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide(9.00 mg, 0.018 mmol), tributyl amine (12.81 μL, 0.054 mmol), and formicacid (1.378 μL, 0.036 mmol), under an argon atmosphere, was addedPd(PPh₃)₂Cl₂ (1.0 mg, 0.898 μmol). The reaction was stirred at 80° C.for 4 h, then diluted with EtOAc and washed with water. The organiclayer was separated and dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The resulting residue waspurified by reverse phase semiprep HPLC (acetonitrile/water, 0.1% TFA)to obtain the title compound as the TFA salt. MS ESI calcd. forC₂₀H₁₈F₃N₄04S [M+H]⁺ 467, found 467. ¹H NMR (400 MHz, CD₃OD): δ2.46-2.56 (m, 1H), 2.98-3.07 (m, 1H), 3.09-3.18 (m, 1H), 4.08 (dd, J=5.8Hz, 11.8 Hz, 1H), 4.34 (dd, J=2.6 Hz, 11.4 Hz, 1H), 4.57 (d, J=5.16 Hz,1H), 7.14-7.18 (m, 1H), 7.24 (dd, J=1.7 Hz, 8.0 Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 7.76 (t, J=6.6 Hz, 1H), 7.80 (m, 2H), 8.29-8.37 (m, 1H), 8.57(d, J=4.6 Hz, 1H), 8.65 (d, J=5.2 Hz, 1H);

Example 91 N-(6-chloro-4-((3S,4R or3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide

This compound was prepared according to the procedure of Example 89 Step1 starting from (3S,4R or3R,4S)-3-(pyridin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol(Intermediate 2, enantiomer A). MS ESI calcd. for C₂₀H₁₇ClF₃N₄O₄S[M+H]⁺501, found 501.

Examples 92-981,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide

Step 1: (E)-7-Bromo-3-((2-phenylthiazol-4-yl)methylene)chroman-4-one

7-Bromochroman-4-one (2.00 g, 8.81 mmol),2-phenylthiazole-4-carbaldehyde (2.00 g, 10.57 mmol), pyrrolidine (0.728ml, 8.81 mmol) and MeOH (20.0 mL) were combined. The reaction mixturewas stirred at room temperature for 16 h. Then the reaction mixture wasdiluted with MeOH (10 mL), and the resulting solid was filtered andwashed with MeOH to give the title compound. MS ESI calcd. forC₁₉H₁₃BrNO₂S [M+H]⁺ 397, found 397.

Step 2: 7-Bromo-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-4-one

To a solution of(E)-7-bromo-3-((2-phenylthiazol-4-yl)methylene)chroman-4-one (1.50 g,3.77 mmol) in anhydrous THF (40 mL) at −20° C., was added slowlymethylmagnesium bromide (3.14 mL, 9.42 mmol). The reaction was stirredfor 5 min, then quenched with brine (10 mL) and extracted with EtOAc(2×15 mL). The combined organic layers were washed with brine (10 mL),dried over sodium sulfate, and concentrated. The crude residue waspurified on silica by combi-flash (EtOAc/n-hexanes: 20-40%) to obtainthe title compound. MS ESI calcd. for C₂₀H₁₇BrNO₂S [M+H]⁺ 414, found414.

Step 3: 7-bromo-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-4-ol

7-Bromo-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-4-one (600 mg, 1.448mmol), sodium tetrahydroborate (110 mg, 2.90 mmol) and MeOH (10 ml) werecombined at 0° C. The reaction mixture was allowed to warm slowly toroom temperature. After stirring for 1 h, the reaction mixture wasconcentrated to remove MeOH, diluted with water (10 mL)/saturated Na₂SO₄(5 mL) and extracted with EtOAc (2×10 mL). The combined organic layerswere dried over sodium sulfate, and concentrated. The resulting residuewas purified on a 100 gram HP C18 Gold reverse phase column (eluent:0-60% acetonitrile/water; flow rate: 50 ml per minute) to obtain7-bromo-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-4-ol as a mixture ofsix isomers (four trans isomers [rac-(trans, syn) and rac-(trans,anti)]) and ˜10% rac-(cis/syn or cis/anti) isomers; MS ESI calcd. forC₂₀H₁₉BrNO₂S [M+H]⁺ 416, found 416); and7-bromo-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-4-ol as a mixture ofrac-(cis/syn or cis/anti) isomers (MS ESI calcd. for C₂₀H₁₉BrNO₂S [M+H]⁺416, found 416).

Step 4:3-(1-(2-phenylthiazol-4-yl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol

To a solution of 7-Bromo-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-4-ol(as a mixture of six isomers, four trans isomers [rac-(trans, syn) andrac-(trans, anti)]) and ˜10% rac-(cis/syn or cis/anti) isomers); 150 mg,0.360 mmol) in 1,4-dioxane (15 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (110 mg,0.432 mmol) and potassium acetate (106 mg, 1.081 mmol). The reaction waspurged with N₂ gas for 10 min, followed by addition of1,1′bis(diphenylphosphino)ferrocene]-dichloro-palladium(II) (26.4 mg,0.036 mmol). The reaction mixture was heated to 80° C. for 14 h. Thenthe reaction solution was cooled to room temperature and concentrated.The resulting crude product was diluted with brine (10 mL) and extractedwith EtOAc (2×10 mL). The combined organic layers were dried over sodiumsulfate, and concentrated to give the title compound as a mixture of sixisomers (four trans isomers [rac-(trans, syn) and rac-(trans, anti)] and˜10% rac-(cis/syn or cis/anti) isomers). MS ESI calcd. for C₂₆H₃₁NO₄S[M+H]⁺ 464, found 464.

Step 5:1.1.1-trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide

3-(1-(2-Phenylthiazol-4-yl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-olas a mixture of six isomers (four trans isomers [rac-(trans, syn) andrac-(trans, anti)]) and ˜10% rac-(cis/syn or cis/anti) isomers; 183 mg,0.395 mmol), and potassium phosphate (209 mg, 0.987 mmol) in THF (8mL)/water (2 mL) were combined and purged N₂ gas for 10 min. ThenChloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(51.7 mg, 0.066 mmol) was added. The reaction was heated to 75° C. for5h. Then the reaction mixture was diluted with saturated NH₄Cl (10 mL)and extracted with EtOAc (2×10 mL). The combined organic layers weredried over sodium sulfate, and concentrated. The resulting residue waspurified on silica by combi-flash (EtOAc/hexanes) to obtain the titlecompound as a mixture of six isomers (four trans isomers [rac-(trans,syn) and rac-(trans, anti)]) and ˜10% rac-(cis/syn or cis/anti)isomers). ¹H NMR (400 MHz, MeOH) δ 7.93-7.79 (m, 2H), 7.42-7.46 (m, 3H),7.32-7.39 (m, 5H), 7.25 (s, 1H), 6.98 (dd, J=7.81 Hz, 1.68 Hz, 1H), 6.82(d, J=1.68 Hz, 1H), 4.90 (d, J=1.75 Hz, 1H), 4.01-4.07 (m, 1H),3.74-3.78 (m, 1H), 3.20-3.24 (m, 1H), 2.37-2.42 (m, 1H), 1.52 (d, J=6.85Hz, 3H). MS ESI calcd. for C₂₇H₂₄F₃N₂O₄S₂ [M+H]⁺ 561, found 561.

Step 6: Chiral Separation of Six Diastereomeric Single Enantiomers of1.1.1-trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide

The mixture of1,1,1-trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-7-yl)phenyl)methane-sulfonamideas a mixture of six isomers (four trans isomers [rac-(trans, syn) andrac-(trans, anti)]) and ˜10% rac-(cis/syn or cis/anti) isomers) wassubjected to chiral separation on SFC (ADH column, 20% EtOH) to separatethe mixture of six isomers/enantiomers into the following singleenantiomers A-F: Enantiomer A (third eluted peak, trans isomer): MS ESIcalcd. for C₂₇H₂₄F₃N₂O₄S₂ [M+H]⁺ 561, found 561; Enantiomer B (fourtheluted peak, trans isomer): MS ESI calcd. for C₂₇H₂₄F₃N₂O₄S₂ [M+H]⁺ 561,found 561; Enantiomer C (fifth eluted peak, trans isomer): MS ESI calcd.for C₂₇H₂₄F₃N₂O₄S₂ [M+H]⁺ 561, found 561; Enantiomer D (sixth elutedpeak, trans isomer): MS ESI calcd. for C₂₇H₂₄F₃N₂O₄S₂ [M+H]⁺ 561, found561; Enantiomer E (first eluted peak, cis isomer): MS ESI calcd. forC₂₇H₂₄F₃N₂O₄S₂ [M+H]⁺ 561, found 561; Enantiomer F (second eluted peak,cis isomer): MS ESI calcd. for C₂₇H₂₄F₃N₂O₄S₂ [M+H]⁺ 561, found 561. Allisomers (Enantiomers A, B, C, D, E and F) were isolated as single pureenantiomers (all stereochemical assignments were tentative).

Examples 99-1051,1,1-trifluoro-N-(4-fluoro-2-(4-hydroxy-3-(1-(pyridin-2-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide (Enantiomers A, B, C, D, E, F)

1,1,1-trifluoro-N-(4-fluoro-2-(4-hydroxy-3-(1-(pyridin-2-yl)ethyl)chroman-7-yl)phenyl)methane-sulfonamideThe title compound as a mixture of six isomers (four trans isomers[rac-(trans, syn) and rac-(trans, anti)]) and ˜24% rac-(cis/syn orcis/anti) isomers) was prepared according to the procedure of Steps 1-5of Example 92. The resulting crude mixture of six isomers(diastereomeric enantiomers) was subjected to chiral separation on SFC(ADH column, 20% EtOH) to give the following single enantiomers:Enantiomer A (second eluted peak, trans isomer. MS ESI calcd. forC₂₃H₁₉F₄N₂O₄S [M−H]⁻ 496, found 495; Enantiomer B (fourth eluted peak,trans isomer): MS ESI calcd. for C₂₃H₁₉F₄N₂O₄S [M−H]⁻ 496, found 495;Enantiomer C (fifth eluted peak, trans isomer): MS ESI calcd. forC₂₃H₁₉F₄N₂O₄S [M−H]⁻ 496, found 495; Enantiomer D (sixth eluted peak,trans isomer): MS ESI calcd. for C₂₃H₁₉F₄N₂O₄S [M−H]⁻ 496, found 495;Enantiomer E (first eluted peak, cis isomer): MS ESI calcd. forC₂₃H₁₉F₄N₂O₄S [M−H]⁻ 496, found 495; Enantiomer F (third eluted peak,cis isomer): MS ESI calcd. for C₂₃H₁₉F₄N₂O₄S [M−H]⁻ 496, found 495. Allisomers (Enantiomers A, B, C, D, E and F) were isolated as single pureenantiomers (all stereochemical assignments were tentative).

Example of a Pharmaceutical Composition

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of the Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

Biological Assay

BLT-1 cAMP Assay

The ability of compounds to antagonize the human BLT1 receptor wasdetermined using a kit to measure changes in intracellular cyclic AMPlevels (cAMP dynamic assay kit, Cisbio Cat. No. 62AM4PEC). HEK293 cellsrecombinantly expressing human BLT1, previously frozen in RecoveryMedium (Life Technologies, Cat. No. 12648-010) were thawed and dilutedinto assay medium (HBSS (Hyclone SH 30268.01), 20 mM HEPES (Gibco15630-106), 800 μM IBMX (Sigma 15879), 0.1% DTPA BSA (Perkin ElmerCR84-100)). The cell suspension was centrifuged at 200×g for 10 min andthen resuspended in fresh assay medium to a density of 2.5×10⁵cells/mL.A Labcyte Echo 550 acoustic dispenser was used to transfer 25 nL of testcompound dissolved in DMSO into the wells of a dry 384-well plate(Greiner 784075). All subsequent liquid additions were performed using aBIORAPTR (FRD; Beckman Coulter). Next, μL of cell suspension was addedand incubated for 20 min. at 37° C. and 5% CO₂ in a humidified plastictray. To test for agonist activity 5 μL of assay buffer containingforskolin (Sigma F-6886. 4 μM for BLT1) was added and incubated for 30minutes at 37° C. and 5% CO₂ in a humidified plastic tray. To test forantagonist activity 5 μL of assay buffer containing forskolin (SigmaF-6886. 4 μM for BLT1) and either LTB₄ (Sigma Aldrich L0517; 2 nM BLT1)was added and incubated for 30 minutes at 37° C. and 5% CO₂ in ahumidified plastic tray.

The levels of cAMP were detected using the CisBio kit following themanufacturer's instructions: cAMP-d2 vial was reconstituted withdistilled water and then diluted accordingly with conjugate & lysisbuffer. 5 μL of cAMP-d2 working solution was added to all of the wellsof the assay plate. cAMP-Cryptate vial was reconstituted with distilledwater and then diluted accordingly with conjugate & lysis buffer. 5 μLof cAMP-Cryptate working solution were added to the assay plate. Theassay plate was shaken for 3 minutes and incubated at room temperaturefor 45 minutes, then read on Perkin Elmer Envision. cAMP standard curveand fit data were plotted using a 4 parameter dose response curvefitting algorithm to fit curve. A 4-parameter curve fit (Max, min, logEC50 and slope) was used to transform fluorescent 665 nm/615 nm ratiosignal to cAMP concentration. After normalization to treated anduntreated controls, the percent effect of signal at each compoundconcentration was calculated. The plot of percent effect versus the logof compound concentration was fit with a 4-parameter concentrationresponse equation to calculate EC₅₀ values. Compound concentrationstested were 10 000, 3 333, 1 111, 370.4, 123.4, 41.2, 13.7, 4.6, 1.5 and0.5 nM with 0.25% residual DMSO.

The compounds of the present invention, including the compounds inExamples 1-105, have EC₅₀ values less than ≤5000 nanomolar (nM) in theBLT-1 cAMP Assay described above. Specific EC₅₀ values in the BLT-1 cAMPAssay are shown in Table I.

TABLE I EC₅₀(nM) Example Number BLT-1 cAMP Assay 2 31 3 2294 4 6 5 9 6240 7 3511 8 21 9 269 10 4536 11 105 12 1653 13 185 14 101 15 994 16 82619 1599 20 215 23 32 24 329 25 412 26 121 27 209 28 2141 29 464 30 41431 1371 32 17 33 53 34 44 35 824 36 737 37 754 38 4 39 1 40 18 41 225 42445 43 64 44 1554 45 1428 46 157 47 1200 48 870 49 275 50 29 51 808 524045 53 69 54 55 55 2016 56 826 57 10 59 15 60 269 61 1337 62 23 63 32064 971 65 47 66 210 67 48 68 5.3 69 30 70 261 71 125 72 2975 73 193 744050 75 235 76 1859 77 118 78 1868 79 35 80 481 81 15 82 119 83 14 841608 85 63 86 156 87 239 88 285 89 965 90 3081 91 2688 92 80 93 6 94 11197 268 99 1 100 72 101 678 102 78 103 1308

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the scope of the invention. For example,effective dosages other than the particular dosages as set forth hereinabove may be applicable as a consequence of variations in responsivenessof the mammal being treated for any of the indications with thecompounds of the invention indicated above. The specific pharmacologicalresponses observed may vary according to and depending upon theparticular active compounds selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein A is selectedfrom the group consisting of: (1) aryl, and (2) heteroaryl, wherein aryland heteroaryl are unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, and halogen; B isselected from the group consisting of: (1) aryl, and (2) heteroaryl,wherein aryl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, halogen and CF₃, and whereinheteroaryl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, halogen, and CF₃; X is selectedfrom the group consisting of: (1) —NHSO₂CF₃, (2) —NHSO₂CH₂CF₃, (3)—NHSO₂CHF₂, (4) —NHSO₂C₁₋₆alkyl, (5) —NHSO₂CH₂C₃₋₆cycloalkyl, and (6)—NHSO₂C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl;Z is selected from the group consisting of: (1) hydrogen, (2) C₁₋₆alkyl,and (3) phenyl, wherein alkyl and phenyl are unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyl;R^(a) is selected from the group consisting of: (1) hydrogen, (2)halogen, and (3) C₁₋₆alkyl; and R^(b) is selected from the groupconsisting of: (1) hydrogen, (2) halogen, and (3) C₁₋₆alkyl.
 2. Thecompound according to claim 1 wherein Z is hydrogen or —C₁₋₆alkyl; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 wherein Z is phenyl, wherein phenyl is unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyl;or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 1 wherein X is selected from the group consisting of: (1)—NHSO₂CF₃, (2) —NHSO₂CH₂CF₃, (3) —NHSO₂CHF₂, (4) —NHSO₂C₁₋₆alkyl, and(5) —NHSO₂C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl are unsubstitutedor substituted with 1-3 substituents independently selected fromC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 5. Thecompound according to claim 1 wherein X is —NHSO₂CF₃; or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 1 wherein A is selected from the group consisting of: (1) phenyl,and (2) heteroaryl, wherein phenyl and heteroaryl are unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, and halogen; or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 1 wherein A is phenyl,wherein phenyl is unsubstituted or substituted with 1-4 substituentsindependently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl and halogen; or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1 wherein A is heteroaryl, wherein heteroaryl is unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl,C₃₋₆cycloalkyl and halogen; or a pharmaceutically acceptable saltthereof.
 9. The compound according to claim 1 wherein A is selected fromthe group consisting of: (1) pyrazole, (2) pyridine, (3) thiophene, (4)thiazole, (5) benzothiophene, (6) triazole, (7) oxazole, (8) pyrazine,(9) thiadiazole, and (10) pyridazine, wherein pyrazole, pyridine,thiophene, thiazole, benzothiophene, triazole, oxazole, pyrazine,thiadiazole, and pyridazine are unsubstituted or substituted with 1-3substituents independently selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, andhalogen; or a pharmaceutically acceptable salt thereof.
 10. The compoundaccording to claim 1 wherein A is pyridine; or a pharmaceuticallyacceptable salt thereof.
 11. The compound according to claim 1 wherein Bis selected from the group consisting of: (1) phenyl, (2) pyrazine, (3)pyridine, and (4) pyridazine, wherein phenyl is unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyl,halogen and CF₃, and wherein pyrazine, pyridine and pyridazine areunsubstituted or substituted with 1-4 substituents independentlyselected from C₁₋₆alkyl, halogen, and CF₃; or a pharmaceuticallyacceptable salt thereof.
 12. The compound according to claim 1 wherein Bis phenyl; or a pharmaceutically acceptable salt thereof.
 13. Thecompound according to claim 1 wherein B is pyridine, wherein pyridine isunsubstituted or substituted with 1-3 substituents independentlyselected from halogen; or a pharmaceutically acceptable salt thereof.14. The compound according to claim 1 wherein R^(a) and R^(b) areindependently selected from the group consisting of: hydrogen, andC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 15. Thecompound according to claim 1 wherein R^(a) and R^(b) are hydrogen; or apharmaceutically acceptable salt thereof.
 16. The compound according toclaim 1 wherein A is selected from the group consisting of: (1) phenyl,and (2) heteroaryl, wherein phenyl and heteroaryl are unsubstituted orsubstituted with 1-4 substituents independently selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, and halogen; B is selected from the group consisting of:(1) phenyl, (2) pyrazine, (3) pyridine, and (4) pyridazine, whereinpyrazine, pyridine and pyridazine are unsubstituted or substituted with1-3 substituents independently selected from C₁₋₆alkyl, halogen, andCF₃; X is selected from the group consisting of: (1) —NHSO₂CF₃, (2)—NHSO₂CH₂CF₃, (3) —NHSO₂CHF₂, (4) —NHSO₂C₁₋₆alkyl, and (5)—NHSO₂C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted orsubstituted with 1-3 substituents independently selected from C₁₋₆alkyl;Z is selected from the group consisting of: (1) hydrogen, and (2)phenyl, wherein phenyl is unsubstituted or substituted with 1-4substituents independently selected from C₁₋₆alkyl; and R^(a) and R^(b)are independently selected from the group consisting of: hydrogen, andC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 17. Thecompound according to claim 1 wherein A is heteroaryl; B is phenyl; X is—NHSO₂CF₃; Z is hydrogen; and R^(a) and R^(b) are hydrogen; or apharmaceutically acceptable salt thereof.
 18. The compound according toclaim 21 selected from: (1)N-(2-((3,4-Rac-cis)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(2)N-(2-((3,4-Rac-trans)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(3)N-(2-((3,4-Rac-cis)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(4)N-(2-((3,4-Rac-trans)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(5)1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-phenylthiophen-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(6)N-(2-((3,4-Rac-trans)-3-((1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(7)1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(pyridin-3-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(8)1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-3-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(9)1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiazol-5-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(10)1,1,1-Trifluoro-N-(2-((3,4-rac-cis)-4-hydroxy-3-(thiazol-5-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(11)1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-methylpyridin-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(12)N-(2-((3,4-Rac-trans)-3-((1H-pyrazol-4-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(13)1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((1-methyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(14)1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(15)1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(1,3-oxazol-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(16)1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(17)N-(2-{(rac-trans)-3-[(2-cyclopropyl-1,3-thiazol-4-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl)-1,1,1-trifluoromethanesulfonamide;(18)1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(1-methyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(19)1,1,1-Trifluoro-N-(2-{(rac-trans)-3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(20)1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(6-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(21)1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(22)1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(23)1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(24)1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((2-phenylthiazol-4-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(25)1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(26) 1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(27)1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(28)1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(pyridazin-3-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methane-sulfonamide;(29)1,1,1-Trifluoro-N-(2-((rac-trans)-3-((5-fluoropyridin-2-yl)methyl)-4-hydroxychroman-7-yl)phenyl)methanesulfonamide;(30)N-(2-((3,4-Rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(31)1,1,1-trifluoro-N-(2-(3,4-rac-cis)-4-hydroxy-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)metha-nesulfonamide;(32)1,1,1-trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiazol-4-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(33)1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(34)N-(2-((3,4-rac-trans)-3-(benzo[b]thiophen-2-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(35)1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(36)1,1,1-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(37)1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(38)1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(39)(2-((3S,4R)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl)chroman-7-yl)phenyl)((trifluoromethyl)sulfonyl)amide;(40)(2-((3R,4S)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl)chroman-7-yl)phenyl)((trifluoromethyl)sulfonyl)amide;(41)1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((2-phenylthiazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(42)1,1,1-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-((2-phenylthiazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(43)1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-((2-phenylthiazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(44)1,1,1-Trifluoro-N-(2-((3,4-trans)-3-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methyl)-4-hydroxychroman-7-yl)phenyl)methanesulfonamide;(45)N-(2-((3,4-trans)-3-((2-(tert-butyl)thiazol-4-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(46)N-(2-((3S,4R)-3-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(47)N-(2-((3R,4S)-3-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;(48)1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((1-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)methanesulfonamide;(49)(2-((3,4-trans)-4-hydroxy-3-((1-phenyl-1H-pyrazol-5-yl)methyl)chroman-7-yl)phenyl)((trifluoromethyl)sulfonyl)amide;(50)1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(1,3-thiazol-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;(51)1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(1,3-thiazol-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;(52)1,1,1-trifluoro-N-(2-{(3S,4R)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(53)1,1,1-trifluoro-N-(2-{(3R,4S)-4-hydroxy-3-[(5-methyl-1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(54) 1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;(55)1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;(56)1,1,1-Trifluoro-N-(2-{(3R,4S)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)-methanesulfonamide;(57)1,1,1-Trifluoro-N-(2-{(3S,4R)-4-hydroxy-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)-methanesulfonamide;(58)N-{2-[(3R,4S)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;(59)N-{2-[(3S,4R)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;(60)1,1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(61)1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(62) 1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(63)1,1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(6-methyl-pyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}-phenyl)methanesulfonamide;(64)1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-((2-phenylthiazol-4-yl)-methyl)chroman-7-yl)-phenyl)methanesulfonamide;(65)1,1,1,-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-((2-phenylthiazol-4-yl)-methyl)chroman-7-yl)-phenyl)methanesulfonamide;(66)1,1,1-trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(1-methyl-1H-pyrazol-5-yl)methyl]-3,4-di-hydro-2H-chromen-7-yl}-phenyl)methanesulfonamide;(67)N-{2-[(3S,4R)-3-(biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;(68)N-{2-[(3R,4S)-3-(biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;(69)1,1,1-Trifluoro-N-(2-{(3,4-trans)-3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl)methanesulfonamide;(70)1,1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl)}phenyl)-methanesulfonamide;(71)1,1,1-trifluoro-N-{2-[(3,4-trans)-4-hydroxy-3-(1H-pyrazol-3-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;(72)N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(73)N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;(74)1,1,1-Trifluoro-N-(3-((3,4-rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyrazin-2-yl)methanesulfonamide;(75)N-(2-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)-1-methylcyclopropane-1-sulfonamide;(76)2,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyrazin-2-yl)ethanesulfonamide;(77)2,2,2-Trifluoro-N-(3-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)ethanesulfonamide;(78)2,2,2-Trifluoro-N-(3-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)ethanesulfonamide;(79)2,2,2-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)ethanesulfonamide;(80)2,2,2-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)ethanesulfonamide;(81)1,1-Difluoro-N-(2-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(82)1,1-Difluoro-N-(2-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide;(83) 1,1,1-Trifluoro-N-(4-fluoro-2-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)phenyl)methanesulfonamide; (84)1,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;(85)1,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;(86)1,1-Difluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;(87)1,1,1-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridin-2-yl)methanesulfonamide;(88)2,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)-5-(trifluoromethyl)pyrazin-2-yl)ethanesulfonamide;(89)N-(6-chloro-4-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide;(90)N-(4-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoro-methanesulfonamide;(91)N-(6-chloro-4-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide;(92)1,1,1-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(1-(2-phenylthiazol-4-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide;and (93)1,1,1-trifluoro-N-(4-fluoro-2-(4-hydroxy-3-(1-(pyridin-2-yl)ethyl)chroman-7-yl)phenyl)methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 20.(canceled)
 21. (canceled)
 22. A method of treating or preventing adisorder, condition or disease that may be responsive to the antagonismof the BLT1 receptor in a patient in need thereof comprisingadministration of a therapeutically effective amount of a compoundaccording to claim
 1. 23. A method of treating type 2 diabetes mellitusin a patient in need of treatment comprising the administration to thepatient of a therapeutically effective amount of a compound of claim 1,or a pharmaceutically acceptable salt thereof.